Achondroplasia. FIG. 1. A young infant with achondroplasia. His head and ventricles are large, although his head circumference is within normal limits for a child with achondroplasia. He had a history of apneic spells, and had “trimming” of his epiglottis. During a later tonsillectomy, he had a presumably vagally mediated asystolic arrest.
Achondroplasia. FIG. 2. The same patient at 7 years of age. He has had a tracheostomy in the interval as well as surgical straightening of his tibias and fibulae.
Short stature, secondary to rhizomelic shortening of the arms and legs. Trunk length is normal. Long bones are shortened. Incomplete extension at the elbow. Hyperextensibility of other joints, especially the knees. Trident hands. Thoracolumbar kyphosis and severe lumbar lordosis. Small pelvis. Bowing of the lower extremities. Occipitalization of C-1. Patients can have a variety of spine abnormalities (see Neuromuscular).
Obesity is often present in both sexes. Glucose intolerance is common. The small maternal pelvis, exaggerated lumbar lordosis, and near-normal fetal size make delivery of women with achondroplasia by cesarean section preferable. The relatively large fetus causes more than usual impingement of the uterus on the diaphragm during pregnancy with reduction in functional residual capacity.
Achondroplastic skeletal remains have been identified in Egypt, which date to 4500 BCE, and achondroplastic dwarf figurines have been discovered among pre-Columbian art dating from approximately 500 BCE.
Recall that despite the child-size stature, patients have intelligence and social skills normal for their chronologic age.
Instability of the cervical spine is rare, but possible. Compression at the cervicomedullary junction can occur in the supine position when the large occiput displaces the head sufficiently forward so that the prominent posterior margin of the foramen magnum impinges on the upper spinal cord or medulla. This can be prevented by placing a bolster under the shoulders. Forty-six percent of patients have spinal involvement, so perioperative neurologic and orthopedic examinations are critical. Monitoring somatosensory evoked potentials may help identify early cord compression in surgery requiring abnormal positioning (14), but false-negative results with a brainstem infarction and with a C-1 cord level have been reported (19), although the data in that case may have been corrupted by excessive isoflurane.
Visualization of the larynx is usually uncomplicated but may be very difficult if there is limited cervical extension. Patients can usually be ventilated by mask, but a good mask fit may be difficult to obtain. The narrow nasopharynx or choanal stenosis can preclude placement of a nasal airway, nasal intubation, or placement of a nasogastric tube. Macroglossia can obstruct the airway, and obstruction can resolve with an oropharyngeal airway. Endotracheal tubes smaller than that estimated by age are often needed, and an approximation based on weight may be more appropriate (19).
Low functional residual capacity can lead to rapid desaturation with the induction of anesthesia. Respiratory status could necessitate an arterial catheter. Patients may have pulmonary hypertension. The presence of tracheo/bronchomalacia and/or obstructive sleep apnea may increase the risk of perioperative respiratory complications, and close monitoring should continue into the postoperative period (1,6). Patients may require postoperative ventilation, and pain control is critical to postoperative respiratory status.
Obesity can predispose to gastroesophageal reflux. Excess skin and subcutaneous tissue may make placement of venous catheters more difficult. Limb deformities may make venous and arterial access difficult. Careful positioning is required because of the hyperextensibility of most joints, especially the knee. Short, thick upper arms can make fixation of an appropriate-sized blood pressure cuff difficult, and falsely high pressures can be displayed by noninvasive monitors. An appropriate blood pressure cuff should cover two-thirds of the upper arm length.
A retrospective study reported very few problems in the management of general anesthesia for patients with achondroplasia (13). Apparent dexmedetomidine-induced polyuric syndrome has been reported in an achondroplastic patient but is unlikely to be related directly to his achondroplasia (2). Despite spinal abnormalities and possible technical difficulties (4), regional anesthesia for cesarean section has been reported, although lower-than-normal volumes of anesthetic are required because of the short stature (approximately 5 to 12 mL) (5,10,12,15–18). Given this range, incremental dosing is important.
1.Dessoffy KE, Modaff P, Pauli RM. Airway malacia in children with achondroplasia. Am J Med Genet A 2014;164:407–414.
2.Greening A, Mathews L, Blair J. Apparent dexmedetomidine-induced polyuric syndrome in an achondroplastic patient undergoing posterior spinal fusion. Anesth Analg 2011;113:1381–1383.
3.Neema PK, Sethuraman M, Vijayakumar A, et al. Sinus venous atrial septal defect closure in an achondroplastic dwarf: anesthetic and cardiopulmonary bypass management issues [Letter]. Paediatr Anaesth 2008;18:998–1000.
4.Burgoyne LL, Laningham F, Zero JT, et al. Unsuccessful lumbar puncture in a paediatric patient with achondroplasia. Anaesth Intensive Care 2007;35:780–783.
5.Mitra S, Dey N, Gomber KK. Emergency Cesarean section in a patient with achondroplasia: an anesthetic diliemma [sic]. J Anesth Clin Pharmacol 2007;23:315–318.
6.Ottonello G, Villa G, Moscatelli A, et al. Noninvasive ventilation in a child affected by achondroplasia respiratory difficulty syndrome. Paediatr Anaesth 2007;17:75–79.
7.Palomero MA, Vargas MC, Pelaez EM, et al. Spinal anaesthesia for emergency caesarean section in an achondroplastic patient [Letter]. Eur J Anaesthesiol 2007;24:981–982.
8.Horton WA. Recent milestones in achondroplasia research. Am J Med Genet A 2006;140:166–169.
9.Krishnan BS, Eipe N, Korula G. Anaesthetic management of a patient with achondroplasia. Paediatr Anaesth 2003;13:547–549.
10.Trikha A, Goyal K, Sadera GS, et al. Combined spinal epidural anaesthesia for vesico-vaginal fistula repair in an achondroplastic dwarf. Anaesth Intensive Care 2002;30:96–98.
11.Sisk EA, Heatley DG, Borowski BJ, et al. Obstructive sleep apnea in children with achondroplasia: surgical and anesthetic considerations. Otolaryngol Head Neck Surg 1999;120:248–254.
12.Morrow MJ, Black IH. Epidural anaesthesia for caesarean section in an achondroplastic dwarf. Br J Anaesth 1998;81:619–621.
13.Monedero P, Garcia-Pedrajas F, Coca I, et al. Is management of anesthesia in achondroplastic dwarfs really a challenge? J Clin Anesth 1997;9:208–212.
14.Cunningham MJ, Ferrari L, Kearse LA Jr, et al. Intraoperative somatosensory evoked potential monitoring in achondroplasia. Paediatr Anaesth 1994;4:129–132.
15.Carstoniu J, Yee I, Halpern S. Epidural anaesthesia for caesarean section in an achondroplastic dwarf. Can J Anaesth 1992;39:708–711.
16.McArthur RDA. Obstetric anaesthesia in an achondroplastic dwarf at a regional hospital. Anaesth Intensive Care 1992;20:376–378.
17.Wardall GJ, Frame WT. Extradural anaesthesia for cesarean section in achondroplasia. Br J Anaesth 1990;64:367–370.
18.Brimacombe JR, Caunt JA. Anaesthesia in a gravid achondroplastic dwarf. Anaesthesia 1990;45:132–134.
19.Mayhew JF, Katz J, Miner M, et al. Anaesthesia for the achondroplastic dwarf. Can Anaesth Soc J 1986;33:216–221.
Acid maltase deficiency
See Pompe disease
MIM #: 200990
This autosomal recessive disorder is marked by polydactyly, intellectual disability, and agenesis of the corpus callosum. The syndrome is caused by mutations in the gene KIF7.
Macrocephaly, protruding occiput and forehead, large anterior fontanelle, defect in the calvarium. Hypoplastic midface. Strabismus, hypertelorism, downslanting palpebral fissures, nystagmus, decreased retinal pigmentation, optic atrophy. Small nose. Malformed ears. Retro- or micrognathia, cleft lip, cleft palate, high-arched palate.
Congenital heart defects.
Severe intellectual disability, agenesis of the corpus callosum, Dandy-Walker malformation (see later), hypotonia, arachnoid cysts, seizures, temporal lobe hypoplasia.
Pre- and postaxial polydactyly, duplication of hallux. Tapered fingers. Toe syndactyly. Bipartite clavicle.
Umbilical and inguinal hernias. Hypospadias, cryptorchidism, micropenis. Rectovaginal fistula.
Postnatal growth retardation.
The gene GLI3 is analogous to a gene in Drosophila that regulates, among other genes, the gooseberry gene.
Direct laryngoscopy and tracheal intubation may be difficult because of a high-arched palate, micrognathia, and crowded dentition related to midface hypoplasia. A laryngeal mask airway has been used successfully when intubation was not possible (2). Clavicular anomalies may make placement of a subclavian venous catheter or an infraclavicular block more difficult. Patients with congenital heart disease should receive an appropriately tailored anesthetic. Anticonvulsant medications should be continued through the perioperative period. Chronic use of anticonvulsant medications as well as abnormal liver function may affect the metabolism of some anesthetic and other drugs.
1.Putoux A, Thomas S, Coene KL, et al. KIF7 mutations cause fetal hydrolethalus and acrocallosal syndrome. Nat Genet 2011;43:601606.
2.Aliki S, Theodosia V, Apostolos A, et al. Anesthetic management of a child with acrocallosal syndrome [Letter]. Paediatr Anaesth 2008;18:1001–1002.
3.Koenig R, Bach A, Woelki U, et al. Spectrum of the acrocallosal syndrome. Am J Med Genet 2002;108:7–11.
Acrocephalopolysyndactyly type II
Acrocephalosyndactyly type I
See Apert syndrome
Acrocephalosyndactyly type II
Included in Apert syndrome
Acrocephalosyndactyly type III
Acrocephalosyndactyly type V
Acrodysostosis I and II
MIM #: 101800, 614613
This autosomal dominant disorder is characterized by intellectual disability, short hands and feet with acrodysostosis (progressive defects in ossification distally), distinctive facies (including a small nose and prominent mandible), and endocrine abnormalities. Acrodysostosis I is due to a heterozygous mutation in the protein kinase A gene (PRKAR1A). Although it had been suggested that this disorder is a variant of pseudohypoparathyroidism (see later), genetic studies have shown that the two disorders are distinct (2,3). Recently, a mutation in the cAMP-specific phosphodiesterase 4D gene (PDE4D) has been identified as another cause of acrodysostosis (acrodysostosis II). Patients with acrodysostosis II are less likely to exhibit endocrine abnormalities.
Brachycephaly. Hypertelorism, optic atrophy, strabismus. Blue eyes have been described in Japanese patients. Small, broad, upturned nose with a low nasal bridge. Hearing deficit common. Flat midface and prominent mandible.
Intellectual disability common. Occasional hydrocephalus.
Mild to moderate short stature is common. Advanced bone age. Upper limbs relatively shorter than lower limbs. Abnormally small vertebrae are susceptible to compression. Scoliosis. Spinal canal stenosis. Short limbs with acrodysostosis. Epiphyses are cone shaped. Short, broad hands, feet, fingers, and toes. Short metatarsals.
Rare renal anomalies. Cryptorchidism. Hypogonadism.
Endocrine abnormalities, including resistance to parathyroid hormone, thyrotropin, calcitonin, gonadotropin, and growth hormone–releasing hormone. Wrinkling of the dorsum of the hands. Pigmented nevi.
May have preoperative endocrine abnormalities, particularly hypocalcemia and hyperphosphatemia. Restriction of movement in the hands and spine may present problems in positioning the patient, and wrinkling of the skin of the hands could make intravenous catheter placement more difficult.
1.Michot C, Le Goff C, Goldenberg A, et al. Exome sequencing identifies PDE4D mutations as another cause of acrodysostosis. Am J Hum Genet 2012;90:740–745.
2.Linglart A, Menguy C, Couvineau A, et al. Recurrent PRKAR1A mutation in acrodysostosis with hormone resistance. N Engl J Med 2011;364:2218–2226.
3.Wilson LC, Oude Luttikhuis ME, Baraitser M, et al. Normal erythrocyte membrane Gs-alpha bioactivity in two unrelated patients with acrodysostosis. J Med Genet 1997;34:133–136.
Acromesomelic dwarfism. (Includes Hunter-Thompson and Maroteaux types)
MIM #: 201250, 602875
These autosomal recessive disorders are characterized by short-limbed dwarfism, a prominent forehead, and lower thoracic kyphosis. The Maroteaux type is caused by a defect in the natriuretic peptide receptor B gene (NPR2). The Hunter-Thompson type is caused by a defect in the gene that encodes growth/differentiation factor-5 (GDF5), also known as cartilage-derived morphogenetic protein 1 (CDMP1), a member of the transforming growth factor-beta (TGF-beta) superfamily. Acromesomelic disorders have disproportionate shortening of the middle (forearms and lower legs) and distal (hands and feet) skeleton. In the Hunter-Thompson form, skeletal elements of the hands or feet are fused, while in the Maroteaux type, all elements are present but have abnormal growth. A third acromesomelic dysplasia is Grebe syndrome (see later).
Macrocephaly, prominent forehead. May have corneal opacities. May have a short nose.
Lower thoracic kyphosis. Clavicles are curved superiorly and thus appear high.
Intelligence is normal. Motor development is often delayed.
Extreme short stature. Short limbs, which are more pronounced distally—the forearms and hands are relatively shorter than the upper arms, and the lower legs are shorter than the upper legs. Short, broad metacarpals, metatarsals, and phalanges. Bowed radius, dislocation of the radial head, limited elbow extension. Joint laxity. Epiphyses are cone shaped. Metaphyses of long bones are flared. Hypoplasia of the ilia and acetabular region in childhood may lead to early osteoarthritis of the hip. Lumbar lordosis. Gibbus deformity.
This Hunter and Thompson are presumably not Hunter Thompson the deceased “gonzo” journalist.
Recall that despite the child-size stature, patients have intelligence that is normal for their chronologic age. Patients might require a smaller than expected endotracheal tube if sized for age. Clavicular anomalies may make placement of a subclavian venous catheter or an infraclavicular block more difficult. Radial anomalies may make placement of a radial arterial catheter more difficult. Careful positioning is required secondary to limited elbow extension and hyperextensibility of most other joints. Spine deformities might make neuraxial techniques more difficult.
1.Huang PC, Chang JH, Shen ML, et al. Management of general anesthesia for a patient with Maroteaux type acromesomelic dysplasia complicated with obstructive sleep apnea syndrome and hereditary myopathy [Letter]. J Anesth 2012;26:640–641.
2.Bartels CF, Bukulmez H, Padayatti P, et al. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Am J Hum Genet 2004;75:27–34.
3.Thomas IT, Lin K, Nandekar M, et al. A human chondrodysplasia due to a mutation in a TGF-beta superfamily member. Nat Genet 1996;12:315–317.
Aplasia cutis congenita; Cutis aplasia
MIM #: 100300
This usually autosomal dominant disorder involves failure of skin development over an area of the scalp (aplasia cutis congenita) and various limb reduction defects. There is wide variability in expression, with some affected people showing only subclinical (i.e., radiographic) evidence of the disease. This disorder is genetically heterogeneous and can be caused by mutations in the ARHGAP31, RBPJ, DOCK6, and EOGT genes.
Failure of development of the skin overlying an area of the scalp (aplasia cutis congenita), usually in the parietal region. There may be single or multiple defects. Defects are usually covered by a thin membrane or by scar tissue or may be ulcerated. Skin grafting may be needed. Skull defects can underlie the scalp defect. Occasional frontonasal cysts. Occasional microphthalmia. Occasional cleft lip or palate.
Adams-Oliver syndrome. FIG. 1. Typical scalp defect in Adams-Oliver syndrome. (Courtesy of Dr. Neil Prose, Department of Dermatology, Duke University.)
Occasional cardiac defects. May have pulmonary hypertension.
There is a risk of hemorrhage or meningitis when the superior sagittal sinus or the dura is exposed by an overlying bony defect. Despite the sometimes large defects in the skull, underlying central nervous system abnormalities have only on occasion been associated with this syndrome. Intelligence is normal.
Mild growth deficiency. Various limb reduction defects including absence of the lower extremity below midcalf. Absence or hypoplasia of the metacarpals, metatarsals, and phalanges. Short terminal phalanges, hypoplastic nails.
Adams-Oliver syndrome. FIG. 2. A CT scan from a more severely affected infant.
Adams-Oliver syndrome. FIG. 3. This shows brain herniation in the infant whose CT scan is shown in Figure 2.
Occasional duplicated renal collecting system.
Cutis marmorata. Dilated scalp veins.
Cutis marmorata and dilated scalp veins suggest that embryonic vascular disruption may play a role in the pathogenesis of the Adams-Oliver syndrome. Aplasia cutis congenita and limb reduction defects are consistent with this hypothesis.
Care should be taken to avoid hemorrhage or infection when the superior sagittal sinus or the dura is exposed by an overlying bony defect. Because of the abnormal local vascularity, skin grafts rather than flaps will be required to close scalp defects. Both scalp and limb reduction defects may make intravenous access more difficult. Patients with congenital heart disease should receive an appropriately tailored anesthetic.
1.Snape KM, Ruddy D, Zenker M, et al. The spectra of clinical phenotypes in aplasia cutis congenita and terminal transverse limb defects. Am J Med Genet A 2009;149:1860–1881.
2.Patel MS, Taylor GP, Bharya S, et al. Abnormal pericyte recruitment as a cause for pulmonary hypertension in Adams-Oliver syndrome. Am J Med Genet A 2004;129:294–299.
3.Zapata HH, Sletten LJ, Pierpont ME. Congenital cardiac malformations in Adams-Oliver syndrome. Clin Genet 1995;47:80–84.
Adenosine deaminase deficiency
MIM #: 102700
This autosomal recessive enzyme deficiency causes one type of severe combined immunodeficiency syndrome (SCIDS, see later) with combined B- and T-cell defects and accounts for approximately one-third of the autosomal recessive cases of SCIDS. The adenosine deaminase (ADA) gene is located on the long arm of chromosome 20, and dozens of mutations have been described. Some mutations allow partial enzyme activity with later onset and survival into adulthood, although with an increased incidence of severe infections. ADA catalyzes the conversion of adenosine to inosine and deoxyadenosine to deoxyinosine. In the absence of adenosine deaminase, the cell converts deoxyadenosine to deoxyadenosine triphosphate (deoxy-ATP), which is toxic to cells by activating enzymes that deplete the cell of ATP and other adenosine nucleotides. Lymphocytes are particularly efficient at this, and in essence poison themselves.
Chronic or recurrent sinus infections.
Chronic or recurrent pulmonary infections, asthma.
Can have hepatic dysfunction—hepatitis with hyperbilirubinemia that resolves with enzyme treatment.
Decreased B, T, and CD4 lymphocytes; recurrent candidiasis; warts; and herpes zoster. Severe susceptibility to disease from live virus immunizations (polio, measles) and bacillus Calmette-Guerin (BCG) vaccine. Variable humoral immunity (normal, hyperactive, or reduced). Can have autoimmune hemolytic anemia. Can develop B-cell lymphoma.
Adenosine deaminase has also been found to be lacking in patients with cartilage-hair hypoplasia syndrome (see later). Patients have been treated successfully with bone marrow transplantation, polyethylene glycol–modified adenosine deaminase (very expensive), and gene therapy with retroviral vectors. Adenosine deaminase is found in all mammals with the exception of the horse.
Careful aseptic technique is particularly important. Transfusion of nonirradiated blood can cause graft versus host disease.
1.Gaspar HB. Gene therapy for ADA-SCID: defining the factors for successful outcome. Blood 2012;120:3628–3629.
2.Aiuti A, Cattaneo F, Galimberti S, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med 2009;360:447–458.
3.Hershfield MS. Genotype is an important determinant of phenotype in adenosine deaminase deficiency. Curr Opin Immunol 2003;15:571–577.
4.Bollinger ME, Arredondo-Vega FX, Santisteban I, et al. Hepatic dysfunction as a complication of adenosine deaminase deficiency. N Engl J Med 1996;334:1367–1371.
Addison-Schilder disease; Siemerling-Creutzfeldt disease. (Includes adrenomyeloneuropathy and neonatal adrenoleukodystrophy)
MIM #: 300100
This X-linked recessive disorder is characterized by adrenal cortical insufficiency and central nervous system demyelination due to the accumulation of very-long-chain fatty acids. Presumably, accumulation of 24- to 30-carbon very-long-chain fatty acids interferes with both myelin formation and adrenal steroid synthesis leading to progressive demyelination and adrenal insufficiency. Stem cell transplantation and gene therapy have led to disease stabilization in early trials. Significant phenotypic variation has been described in identical twins with adrenoleukodystrophy, suggesting that nongenetic factors are important in the phenotypic expression. At least seven phenotypic types have been described in males and five in female carriers. One phenotypic variant has been termed adrenomyeloneuropathy (MIM #: 300100). Patients with adrenomyeloneuropathy present with neurologic findings in adulthood, and with evidence of long-standing hypersecretion of adrenocorticotropic hormone (ACTH). The gene responsible for adrenoleukodystrophy is ABCD1, which is a member of the ATP-binding cassette superfamily. These produce a variety of proteins, which translocate a variety of proteins across intra- and extracellular membranes. The gene responsible for cystic fibrosis is another member of this family.
Adrenoleukodystrophy is one of the leukodystrophies, the others of which are metachromatic leukodystrophy, Krabbe disease, Canavan disease, Pelizaeus-Merzbacher disease, and Alexander disease (see later for all).
Neonatal adrenoleukodystrophy (MIM #: 601539) is an autosomal recessive peroxisomal biogenesis disorder, related to Zellweger syndrome and infantile Refsum disease (see later for both). Various mutations in the peroxin gene-1 (PEX1), which is required for transportation of proteins into peroxisomes, lead to infantile Refsum disease, neonatal adrenoleukodystrophy, and Zellweger syndrome. Together, these disorders may represent a continuum of peroxisome biogenesis disorders, with Zellweger syndrome being the most severe, neonatal adrenoleukodystrophy intermediate, and infantile Refsum disease the least severe. Neonatal adrenoleukodystrophy leads to absent or nearly absent peroxisomes, with a deficiency of all of the peroxisomal β-oxidation enzymes. Functions of peroxisomes include synthesis of cell membrane components (particularly constituents of myelin), bile acid synthesis, and fatty acid metabolism. Children with neonatal adrenoleukodystrophy do not usually live beyond their teens.
Adrenoleukodystrophy: Visual disturbances, including decreased acuity with or without visual field defects, optic atrophy. May have Balint syndrome (a neuropsychological paralysis of visual fixation, optic ataxia, and relatively intact vision). There is an increased incidence of color blindness, presumably because of a very close linkage with the color blindness gene(s). Cognitive hearing loss.
Neonatal adrenoleukodystrophy: Retinopathy, impaired hearing. Neonatal cataracts. Esotropia. Broad nasal bridge. Low-set ears. High-arched palate.
Adrenoleukodystrophy: Severe mental and motor delay, and patients may lose milestones between 3 and 5 years of age. Severe hypotonia. Enlarged ventricles, atrophy of the pons and cerebellum. May have seizures. May have behavioral disturbances, difficulty understanding speech in a noisy environment (impaired auditory discrimination), parietal disturbances (including dressing apraxia), poor body orientation in space, diminished graphesthesia. May have spastic paraplegia, peripheral neuropathy, limb and truncal ataxia. Nerve conduction studies may be abnormal. Treatment of adrenal insufficiency with steroids does not affect the severity or progression of the neurologic disease.
Neonatal adrenoleukodystrophy: Intellectual disability, motor delay, seizures. Extent of neurologic involvement is variable, ranging from a stable handicap with some intellectual disability to severe intellectual disability, psychomotor delay, and seizures.
Liver function is typically abnormal (but not as abnormal as in the related Zellweger syndrome). Patients may have gastroesophageal reflux. Hypogonadism with impotence.
The adrenal response to an ACTH challenge may be abnormal, but adrenal insufficiency is less common. Hyperpigmentation of the skin from oversecretion of ACTH.
Purported success in treating this disease with a dietary supplement (“Lorenzo’s oil”) was the basis for a popular film (of the same name) in 1992. While this therapy can normalize very-long-chain fatty acids in blood, it does not affect disease progression. It may, however, reduce the risk of developing brain abnormalities on MRI scan in asymptomatic boys. Bone marrow transplantation and gene therapy have been investigated as treatments.
Thomas Addison (the same Addison of Addison’s disease) committed suicide in 1860 at the age of 65 by jumping out of a window of his villa.
Keep in mind that patients will likely have impaired vision and/or hearing. Patients may have electrolyte imbalances secondary to chronic steroid replacement therapy. Sedative premedication increases the risk of airway obstruction in patients with significant hypotonia. Patients are at risk for perioperative aspiration because of airway hypotonia and gastroesophageal reflux. The risk of excessive potassium release with succinylcholine is unknown but is theoretically possible in bedridden patients with atrophic muscles. One patient has been reported with limited mouth opening who required fiberoptic intubation (5). Patients require careful perioperative positioning and padding secondary to demineralization of bones and ligamentous laxity due to the hypotonia. Patients should be observed closely in the postanesthesia care unit for evidence of airway obstruction from residual anesthetic.
Phenothiazines, butyrophenones, metoclopramide, and other dopaminergic blockers may exacerbate movement disorders. Ondansetron should be safe as an antiemetic because it does not have antidopaminergic effects. Propofol should be used with caution in patients with peroxisomal disorders as they may be at higher risk for developing propofol infusion syndrome (1). Anticonvulsant medications should be continued through the perioperative period. Chronic use of anticonvulsant medications as well as abnormal liver function may affect the metabolism of some anesthetic and other drugs. Adrenal response to stress may be inadequate, and patients may require perioperative stress doses of steroids.
Because insults or injuries to the brain may accelerate demyelination and exacerbate neurologic symptoms, the risk of neurologic surgery is unknown. A teenage patient with only minimal symptoms experienced significant worsening of his disease after cardiopulmonary bypass to correct a ventricular septal defect (9). On the other hand, hemodynamic and hormonal responses to anesthesia and minor surgery were normal in an otherwise asymptomatic child (11).
1.Karaman Y, Goktay A, Agin H, et al. Propofol infusion syndrome or adrenoleukodystrophy? Paediatr Anaesth 2013;23:368–370.
2.Waterman HR, Ebberink MS. Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim Biophys Acta 2012;1822:1430–1441.
3.Kuisle AM, Gauguet S, Karlin LI, et al. Postoperative adrenal crisis in an adolescent with Loeys-Dietz syndrome and undiagnosed adrenoleukodystrophy. Can J Anaesth 2011;58:392–395.
4.Leykin Y, Sanfilippo F, Crespi L, et al. Perioperative management of an adult with childhood cerebral X-linked adrenoleukodystrophy [Letter]. Eur J Anaesthesiol 2010;27:214–216.
5.Hamdiye CT, Yavuz G, Kamil T, et al. Anesthesia management of a child with adrenoleukodystrophy [Letter]. Paediatr Anaesth 2006;16:221–222.
6.Moser HW, Raymond GV, Dubey P. Adrenoleukodystrophy: new approaches to a neurodegenerative disease. JAMA 2005;294: 3131–3134.
7.Dobson G, Lyons J. Anaesthesia for a life-limited child with adrenoleukodystrophy. Eur J Anaesthesiol 2004;21:78–79.
8.Kindopp AS, Ashbury T. Anaesthetic management of an adult patient with X-linked adrenoleukodystrophy. Can J Anaesth 1998;45:990–992.
9.Luciani GB, Pessotto R, Mazzucco A. Adrenoleukodystrophy presenting as postperfusion syndrome [Letter]. N Engl J Med 1997;336:731–732.
10.Schwartz RE, Stayer SA, Pasquariello CA, et al. Anaesthesia for the patient with neonatal adrenoleukodystrophy. Can J Anaesth 1994;41:56–58.
11.Nishina K, Mikawa K, Maekawa N, et al. Anaesthetic considerations in a child with leukodystrophy. Paediatr Anaesth 1993;3:313–316.
12.Tobias JD. Anaesthetic considerations for the child with leukodystrophy. Can J Anaesth 1992;39:394–397.
Included in adrenoleukodystrophy
Hay-Wells ectodermal dysplasia
MIM #: 106260
This autosomal dominant ectodermal dysplasia is associated with cleft lip and palate and congenital filiform fusion of the eyelids. AEC stands for Ankyloblepharon, Ectodermal defects, and Cleft lip and palate. The syndrome is due to defects in the tumor protein gene TP63. There is marked variability of clinical expression. Patients with Rapp-Hodgkin ectodermal dysplasia (see later) and some patients with EEC syndrome (see later) have defects in the same gene.
Oval facies with flattened midface and broad nasal bridge. Scalp erosions. Congenital adhesions between the eyelids with filamentous bands (ankyloblepharon filiforme adnatum). Anomalies of the eye not associated with the tissue bands. Thin eyelashes. Photophobia common. Atretic lacrimal ducts. Otitis media is common. Conductive hearing loss, atretic external auditory canals. Cup-shaped ears. Abnormal dentition, including conical and widely spaced teeth, hypodontia, anodontia. Cleft lip or palate. May have trismus.
Rare patent ductus arteriosus or ventricular septal defect.
Syndactyly, hammer toe deformities.
Hypospadias, micropenis, vaginal dryness.
Ectodermal defects including hyperkeratosis and palmar and plantar keratoderma. Red, cracking skin at birth. Hyperpigmentation. Coarse, wiry, and sparse hair. Dystrophic, hypoplastic, thin, or absent nails. Sweat gland deficiency or dysfunction. Sparse body hair. Scalp infections are common. Supernumerary nipples.
Heat intolerance is common because of poorly functioning sweat glands. There is some capacity to produce sweat, so hyperthermia is not usually a problem. Teeth should be assessed carefully preoperatively because of the likelihood of abnormal dentition.
1.Fete M, van Bokhoven H, Clements SE, et al. International Research Symposium on Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) Syndrome. Am J Med Genet A 2009;149:1885–1893.
2.Propst EJ, Campisi P, Papsin BC. Head and neck manifestations of Hay-Wells syndrome. Otolaryngol Head Neck Surg 2005;132:165–166.
MIM #: 304050
This syndrome is seen only in girls (with the exception of one boy with an XXY karyotype), indicating an X-linked dominant mode of inheritance that is lethal in the hemizygous male. The main features are infantile spasms, agenesis of the corpus callosum, and chorioretinopathy. The gene responsible for this disorder is located on the short arm of the X chromosome (Xp22). The gene product is unknown. Most patients die in adolescence or early adulthood.
Microcephaly. Facial asymmetry. Chorioretinopathy marked by chorioretinal lacunae (holes). Microphthalmia, small optic nerves, and chiasm. Retinal detachment. Cataracts. Coloboma. Nystagmus. Prominent premaxilla, upturned nasal tip. Occasional cleft lip or palate.
Kyphoscoliosis may adversely affect pulmonary status. Rib abnormalities include absent, extra, fused, or bifid ribs.
Microcephaly, severe intellectual disability. Partial or total agenesis of the corpus callosum. Electroencephalographic evidence of independent activity of right and left hemispheres. Abnormalities of the cerebrum, cerebellum, and ventricles. Polymicrogyria, intracranial cysts. Infantile spasms progressing to other seizure types by 2 years of age. Hypotonia. May be associated with the development of central nervous system tumors. Dandy-Walker or Arnold-Chiari malformations.
Kyphoscoliosis. Vertebral anomalies include spina bifida, hemivertebrae, and abnormally shaped vertebrae. Scoliosis. Proximally placed thumbs.
Scalp lipomas. Cavernous hemangiomas. Precocious puberty. A variety of tumors including hepatoblastoma, teratoma, embryonal carcinoma, and angiosarcoma.
Craniofacial features may make direct laryngoscopy and tracheal intubation difficult. Because of their neurologic status, patients are at risk for aspiration. Recurrent pneumonia is common, and pulmonary status can be further compromised by kyphoscoliosis. Patients usually have significant visual impairment. In one reported case in the anesthesia literature, caudal block was impossible due to abnormal vertebral anatomy, and intravenous cannulation was not possible due to “generalized hypotrophia” of subcutaneous tissues (6). Chronic use of anticonvulsant medications may affect the metabolism of some anesthetic drugs.
1.Terakawa Y, Miwa T, Mizuno Y. Anesthetic management of a child with Aicardi syndrome undergoing laparoscopic Nissen’s fundoplication: a case report. J Anesth 2011;25:123–126.
2.Mayhew J. Anesthesia in a child with Aicardi syndrome [Letter]. Paediatr Anaesth 2007;17:1223.
3.Aicardi J. Aicardi syndrome. Brain Dev 2005;27:164–171.
4.Gooden CK, Pate VA, Kavee R. Anesthetic management of a child with Aicardi syndrome [Letter]. Paediatr Anaesth 2005;15:172–173.
5.Sutton VR, Hopkin BJ, Eble TN, et al. Facial and physical features of Aicardi syndrome: infants to teenagers. Am J Med Genet A 2005;138:254–258.
6.Iacobucci T, Galeone M, de Francisi G. Anaesthesia management in a patient with Aicardi’s syndrome [Letter]. Anaesthesia 2003;58:95.
MIM #: 118450
This disease involves primarily the liver (a paucity of intrahepatic bile ducts), heart, and pulmonary arteries. Additional features include characteristic facies, skeletal abnormalities, and renal anomalies. It is an autosomal dominant disorder with incomplete penetrance leading to marked variability in expression. There is genetic heterogeneity, with most cases being due to a defect in the gene Jagged 1 (JAG1), which produces a ligand for the protein “Notch 1,” a transmembrane receptor involved in cell fate decisions. JAG1 is highly expressed in the developing heart and vascular structures, corresponding to the areas of observed clinical defects. A smaller number of patients have a defect in the NOTCH2 gene. Renal involvement is common, and explained by the fact that Notch signaling is involved in the development of the renal system. Liver transplantation has been used successfully in this disorder.
Broad forehead. Long, thin face. Eccentric pupils, deep-set eyes, chorioretinal atrophy, and pigment clumping. Posterior embryotoxon of the eye. Bulbous tip of the nose. Pointed mandible.
Pulmonary valvar and peripheral pulmonary artery stenosis. Occasional tetralogy of Fallot, atrial septal defect, or ventricular septal defect. Abdominal coarctation has been reported.
Poor school performance. Absent deep tendon reflexes. Intracranial hemorrhage has been reported spontaneously or after minor trauma. Hepatic encephalopathy with severe hepatic disease. Can have carotid and intracranial artery aneurysms.
Growth retardation. Butterfly vertebrae, decrease in the interpedicular distances of the lumbar spine. Foreshortening of the fingers. Recurrent and/or poorly healing long bone fractures.
Intrahepatic biliary hypoplasia or atresia with cholestasis. The absence of intrahepatic biliary ducts is not congenital. There appears to be early cholestasis, portal inflammation, and inflammation of intralobular bile ducts, followed by loss of biliary ducts. Patients can have cirrhosis with portal hypertension and hypersplenism. Hepatocellular carcinoma can develop. Renal dysplasia, renal tubular acidosis, vesicoureteral reflux. There can be renal artery stenosis with systemic hypertension.
Alagille syndrome. This 12-month-old girl has a secundum atrial septal defect and a mild hepatic duct problem. She has a history of easily becoming hypoglycemic. (The blue mark over her eye is a pen mark to indicate the side of surgery.)
Hypercholesterolemia and hyperlipidemia with xanthomas of the skin. Essential fatty acid deficiency and vitamin K deficiency from inadequate absorption. Pruritus from cholestasis. A bleeding dyscrasia is not limited solely to intracranial bleeding. Abnormal and excessive bleeding can occur spontaneously or can be intraoperative. Bleeding postoperatively, even after a minor procedure, has been fatal. The etiology is unclear, and hemostatic tests are normal. The dyscrasia could be related to the defect in JAG1, which is widely expressed in endothelium and megakaryocytes.
Baseline cardiac status should be evaluated preoperatively. Patients with congenital heart disease should receive an appropriately tailored anesthetic. Renal and hepatic function can be abnormal. Renal insufficiency has implications for perioperative fluid management and the choice of anesthetic drugs. Hepatic dysfunction can lead to abnormalities in the protein binding of some anesthetic drugs. Vitamin K deficiency (from malabsorption) can lead to clotting abnormalities. Regional anesthesia techniques are contraindicated in the face of abnormal coagulation. Esophageal varices can develop in patients with cirrhosis, so nasogastric tubes and transesophageal echocardiography probes should be passed with caution. Excessive perioperative bleeding is possible.
1.Turpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet 2012;20:251–257.
2.Rahmoune FC, Bruyere M, Tecsy M, et al. Alagille syndrome and pregnancy: anesthetic management for cesarean section. Int J Obstet Anesth 2011;20:355–358.
3.Yildiz TS, Yumuk NO, Baykal D, et al. Alagille syndrome and anesthesia management [Letter]. Paediatr Anaesth 2007;17:91–92.
4.Marshall L, Mayhew JF. Anesthesia for a child with Alagille syndrome [Letter]. Paediatr Anaesth 2005;15:256–257.
5.Subramaniam K, Myers LB. Combined general and epidural anesthesia for a child with Alagille syndrome: a case report. Paediatr Anaesth 2004;14:787–791.
6.Lykavieris P, Crosnier C, Trichet C, et al. Bleeding tendency in children with Alagille syndrome. Pediatrics 2003;111:167–170.
7.Png K, Veyckemans F, De Kock M, et al. Hemodynamic changes in patients with Alagille’s syndrome during orthotopic liver transplantation. Anesth Analg 1999;89:1137–1142.
8.Choudhry DK, Rehman MA, Schwartz RE, et al. The Alagille’s syndrome and its anaesthetic considerations. Paediatr Anaesth 1998;8:79–82.
MIM #: 203100, 606952, 203200
There are a variety of types of albinism, as a number of genes are involved in the full melanin biochemical and metabolic pathway. The most common forms are the types of oculocutaneous albinism, which are autosomal recessive. Type I oculocutaneous albinism is due to an abnormality in the gene for tyrosinase. Tyrosinase catalyzes the conversion of tyrosine into dopa (3,4-dihydroxyphenylalanine), which is a precursor of melanin. Patients with type IA disease never synthesize melanin in any tissue. Patients with type IB disease have a mutation that allows some residual synthetic activity. This form has more phenotypic variability, and in some people, pigmentation can approach normal. One variant of type IB is temperature sensitive, with pigmented arm and leg hair, but white scalp and axillary hair. Type II disease is particularly common in equatorial Africa. It has been suggested that the responsible gene for type II disease is a human analog of the mouse pink-eyed dilution gene. There is phenotypic variation with type II disease, and the phenotype can also be affected by the underlying constitutional pigment background. Albinism occurs in all racial groups.
Absence of retinal pigment (producing a pronounced red reflex). The iris is blue, thin, without a cartwheel effect, and the lens can be seen through it. Some iris pigment can develop in type IB and in type II. Photophobia, nystagmus, strabismus, hypoplasia of the fovea, visual loss.
The skin and hair lack pigmentation in type IA. In type IB, there can be some pigment developing with time. The hair is white or, after prolonged exposure to sunlight, very, very light blond in type IA and can become blond or brown in type IB. Hair can on occasion be reddish in type II and can also darken with age. Melanocytes are present but do not contain pigment. There is increased susceptibility to skin neoplasia, but less so in subtypes in which lentigines, or pigmented freckles, can develop.
Well-known albinos include (purportedly) Noah, of flood fame (4) and the Reverend Dr. Spooner, who gave his name to the term “spoonerism.” It is suggested that his speech aberration was related to his nystagmus, which caused a jumbling of information on the printed page. Albinism was one of the four inborn errors of metabolism (the others being alkaptonuria, cystinuria, and pentosuria) discussed by Garrod in his famous series of lectures in 1902 (5).
It is thought that the temperature-sensitive type IB disease is analogous to that in Siamese cats and the Himalayan mouse, which have tyrosinase mutations that make the enzyme sensitive to higher temperatures, such that melanin synthesis takes place in the cooler areas of the body.
Consideration should be given to patients with photophobia in brightly lit operating rooms.
1.Simeonov DR, Wang X, Wang C, et al. DNA variations in oculocutaneous albinism: an updated mutation list and current outstanding issues in molecular diagnostics. Hum Mutat 2013;34:827–835.
2.Rikke BA, Simpson VJ, Montoliu L, et al. No effect of albinism on sedative-hypnotic sensitivity to ethanol and anesthetics. Alcohol Clin Exp Res 2001;25:171–176.
3.Biswas S, Lloyd IC. Oculocutaneous albinism. Arch Dis Child 1999;80:565–569.
4.Sorsby A. Noah: an albino. BMJ 1958;2:1587–1589.
5.Garrod AE. The incidence of alkaptonuria: a study in individuality. Lancet 1902;2:1616–1620.
Albright hereditary osteodystrophy
Note: This is a distinct entity from McCune-Albright syndrome.
Aldehyde oxidase deficiency
Included in Molybdenum cofactor deficiency
MIM #: 203450
This likely autosomal dominant leukodystrophy is characterized by megalencephaly (a large head) in infancy and progressive spasticity and dementia. Its features are similar to Canavan disease (see later). The responsible gene encodes glial fibrillary acidic protein (GFAP), which is the primary intermediate filament protein synthesized in mature astrocytes. There are infantile, juvenile, and adult forms, all having defects in this gene. The infantile form is most common. Most patients die within 10 years of diagnosis. The juvenile form is more slowly progressive, and the adult form is more heterogeneous.
The other leukodystrophies include adrenoleukodystrophy, metachromatic leukodystrophy, Krabbe disease, Canavan disease, and Pelizaeus-Merzbacher disease.
Megalencephaly in infancy. Copious oral secretions.
Seizures, choreoathetosis, progressive spasticity and dementia, demyelination, ataxia. Can have hydrocephalus.
Increased incidence of gastroesophageal reflux.
Histologically, Alexander disease is characterized by the presence of Rosenthal fibers (tapered eosinophilic rods) in cortical white matter astrocytes.
Gastroesophageal reflux, copious oral secretions, and poor airway tone increase the risk of perioperative aspiration. Consideration should be given to anticholinergic premedication to dry oral secretions. Careful perioperative positioning and padding is important in these patients with poor nutrition. The risk of excessive potassium release with succinylcholine is unknown but is theoretically possible in bedridden patients with atrophic muscles. Anticonvulsant medications need to be continued (or a parenteral form substituted) in the perioperative period and may alter the metabolism of some anesthetic drugs. Copious secretions and airway hypotonia make close postoperative observation of airway adequacy particularly important.
Phenothiazines, butyrophenones, metoclopramide, and other dopaminergic blockers should be avoided because they may exacerbate movement disorders. Ondansetron ought to be safe as an antiemetic because it does not have antidopaminergic effects.
1.Hanefeld FA. Alexander disease: past and present. Cell Mol Life Sci 2004;61:2750–2752.
2.Johnson AB, Brenner M. Alexander’s disease: clinical, pathologic, and genetic features. J Child Neurol 2003;18:625–632.
3.Aicardi J. The inherited leukodystrophies: a clinical overview. J Inherit Metab Dis 1993;16:733–743.
4.Tobias JD. Anaesthetic considerations for the child with leukodystrophy. Can J Anaesth 1992;39:394–397.
MIM #: 203500
This autosomal recessive disease is due to an abnormality in the gene for homogentisic acid oxidase (homogentisate 1,2-dioxygenase). This enzyme is part of the tyrosine and phenylalanine degradation pathways and catalyzes the conversion of homogentisic acid to maleylacetoacetic acid. Deficiency of this enzyme causes accumulation of homogentisic acid (“alkapton”). There is abnormal pigmentation (ochronosis) of a variety of tissues. Pigmentary changes are probably due to a polymer derived from homogentisic acid, although its exact structure is not known.
Corneal pigmentation in older adults. One of the hallmarks of the early descriptions was dark (ochronotic) staining of the ear cartilage, also seen primarily in adults. Ear cartilage can calcify.
Ochronosis of the aortic valve has been described, and mitral involvement has also been described. Aortic staining. There is increased generalized atherosclerosis and coronary artery calcification, and aortic and mitral annular calcification. May develop aortic valve stenosis.
Alcaptonuria. FIG. 1. Ochronotic staining of the external ear in an adult with alkaptonuria. (Courtesy of Dr. Kenneth E. Greer, Department of Dermatology, University of Virginia Health System.)