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Syndrome of the Month X Linked Hydrocephalus and MASA Syndrome

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Syndrome of the Month X Linked Hydrocephalus and MASA Syndrome _f Med Genet 1996;33: 59-65 59 Syndrome of the month J Med Genet: first published as 10.1136/jmg.33.1.59 on 1 January 1996. Downloaded from X linked hydrocephalus and MASA syndrome Sue Kenwrick, Monique Jouet, Dian Donnai Abstract or early mortality. The degree and progression X linked hydrocephalus and MASA syn- of hydrocephalus in these families is highly drome are clinically related, neurological variable with some males not presenting with disorders with an X linked recessive mode symptoms of increased intracranial pressure of inheritance. Although originally de- or macrocephaly despite enlargement of scribed as distinct entities, their similarity ventricles.21017 In general, prominent vent- has become apparent as the number of ricular dilatation and progressive hydro- reported families has increased and a high cephalus is associated with early mortality, degree ofintra- and interfamilial variation whereas mild enlargement and arrest is con- in clinical signs noted for both disorders. sistent with long survival. Consideration of this clinical overlap to- Valve insertion is an effective treatment for gether with finding that genes for both relieving high pressure hydrocephalus and im- diseases map to the same chromosomal proving life expectancy; however, survivors are band (Xq28) led to the hypothesis that they always late in meeting their developmental were caused by mutation at the same locus. milestones. They are mentally retarded with This was confirmed by identification of highly variable IQs ranging from "too low to mutations in patients with X linked hydro- test" to over 701820 and exhibit variable degrees cephalus and MASA syndrome within the of spasticity with increased tone and hy- gene for neural cell adhesion molecule Li. perreflexia, particularly in the lower limbs. Re- Here we review the clinical and genetic flexes and tone may be normal in the arms in characteristics of these disorders and the the presence of marked lower limb spasticity.1 underlying molecular defects in the LI These observations contrast with those de- gene. scribed for non-X linked hydrocephalus where (JrMed Genet 1996;33:59-65) the majority of surviving cases have normal http://jmg.bmj.com/ intelligence and little motor impairment.2 Key words: hydrocephalus; X linked; MASA syndrome. Flexion-adduction deformities ofthe thumbs (clasped or adducted thumbs) are frequently but not always observed (Halliday et al? re- X linked hydrocephalus ported clasped thumbs in 44% of cases) and HISTORY may be associated with agenesis or hypoplasia X linked recessive hydrocephalus is the most of the abductor or extensor muscles of the on September 30, 2021 by guest. Protected copyright. common form of hereditary hydrocephalus thumb.2122 The existence of affected subjects (McKusick No 30700), with an incidence of without obviously abnormal thumbs, and the approximately 1 in 30 000, and accounting for presence of this feature in other syndromes2324 between 2% and 15% of primary idiopathic means that this cannot be relied upon as a hydrocephalus in newborn males.12 It was first diagnostic sign. described in detail in a single large family by A wide variety of brain malformations has Bickers and Adams in 19493 and rediscovered been reported in association with X linked as a sex linked syndrome by Edwards in 1961.14 hydrocephalus including agenesis ofthe corpus University of Since then, over 35 families have been reported callosum or septum pellucidum, fusion of the Cambridge and the existence of an X linked recessive form thalamic fornices, colliculi and corpora quad- Department of of Medicine, Level 5, hydrocephalus is well established.5-'5 rigemina, and absence or hypoplasia of the Addenbrooke's corticospinal tract (CST), as assessed by histo- Hospital, Hills Road, logical analysis ofthe pyramids in cross sections Cambridge CB2 2QQ, UK CLINICAL FEATURES of the medulla.4825-28 The latter observation S Kenwrick X linked hydrocephalus is associated with a provides an explanation for the observed spas- M Jouet wide variation in severity and spectrum of clin- ticity in this disease as increased tone with Department of ical signs and symptoms both within and be- hyperreflexia are characteristic signs of CST Clinical Genetics, tween families. Onset of hydrocephalus often damage. The value of bilateral absence of pyr- St Mary's Hospital, occurs in utero although its appearance may be amids (BAOP) as an indicator of X linked Whitworth Park, Manchester M13 OJH, too late for detection during routine ultrasound hydrocephalus was investigated by Chow25 and UK scanning even at 20 weeks' gestation.10131416 Halliday et al.2 They determined that an as- D Donnai Accumulation of cerebrospinal fluid (CSF) is sociation exists between BAOP and X linked Correspondence to: associated mainly with the lateral and third hydrocephalus although the sample size was Dr Kenwrick. cerebral ventricles and often results in stillbirth small. Nine out of nine patients with clear or 60 Kenwrick, _rouet, Donnai "probable" (by clinical criteria) X linked dis- deficit in development of expressive relative to ease were found to have absent pyramids receptive language. Additional clinical signs whereas six out of six control male cases of include optic atrophy, lordosis, scoliosis, tor- congenital hydrocephalus were not. BAOP'is ticollis, cleft palate, seizures, inguinal hernia, J Med Genet: first published as 10.1136/jmg.33.1.59 on 1 January 1996. Downloaded from not restricted to cases of X linked hydro- and urinary tract abnormalities. Although cephalus and can be found in other congenital MASA is not defined as including hydro- conditions, such as holoprosencephaly and cephalus, imaging in a limited number of hydranencephaly. Nevertheless, the un- patients has shown enlargement of cerebral common nature of BAOP means that it de- ventricles638 and a variety of other brain mal- serves special attention when assessing isolated formations including agenesis of the corpus cases ofhydrocephalus for the possibility of the callosum. hereditary disorder. The early suspicion that X linked hydro- Stenosis of the aqueduct of Sylvius was ori- cephalus and MASA syndrome are caused by ginally thought to be the primary cause of the same X linked locus3839 was reinforced by hydrocephalus as it was observed in several of the observation that both are the result ofgenes the first patients characterised in detail.34 The in the same subchromosomal band (see below) acronym HSAS (for hydrocephalus owing to and reports of single families with both MASA stenosis of the aqueduct of Sylvius) was there- and cotigenital hydrocephalus cases.38"4 fore adopted. Although the aqueduct has been found to be patent in several subsequent ex- amples,5 1422 accurate measurements have rarely Genetics been obtained. Although a degree ofaqueductal X linked hydrocephalus and MASA syndrome stenosis may well contribute to X linked hydro- behave as classical X linked recessive disorders cephalus it cannot be considered diagnostic for with very few carrier females showing signs of the hereditary condition as it is found in up to disease. Preferential inactivation of one X in 40% of patients with hydrocephalus.7 lymphocytes has been shown in manifesting A variety of ocular, musculoskeletal, and carriers of one family suggesting that non-ran- neurological abnormalities have also been dom X inactivation is responsible for the reported in cases of X linked hydrocephalus phenotype in females.34 including nystagmus, ptosis, optic atrophy, sco- The search for a single gene responsible for liosis, torticollis, lumbar lordosis, and seizures. X linked hydrocephalus and MASA syndrome There are no consistent distinguishing began in earnest when genetic linkage analysis facial characteristics although prominent ears provided evidence for loci for both syndromes have been reported.' 18 in subchromosomal band Xq28 with little in- Thus, X linked hydrocephalus is associated dication ofgenetic heterogeneity.3 35-37 39 42 Fur- with an extremely wide variation in severity ther pedigree analysis allowed refinement of and clinical signs. Overall the most consistent the relevant interval to approximately 1 5 me- features are hydrocephalus, mental retardation, gabases ofgenomic DNA between polymorphic and lower limb spasticity consistent with upper markers DXS52 and DXS605,71"538 a region http://jmg.bmj.com/ motor neurone damage (fig 1). containing the gene for neural cell adhesion molecule LI.4 Assessment of this gene in X linked hydrocephalus and MASA syndrome MASA syndrome families provided the final proof that the two HISTORY disorders are indeed caused by mutation at a The term MASA syndrome (McKusick single locus in Xq28. 303350), an acronym for Mental retardation, on September 30, 2021 by guest. Protected copyright. Aphasia, Shuffling gait, and Adducted thumbs, was coined by Bianchine and Lewis30 in 1974 Neural cell adhesion molecule LI to describe the tetrad of X linked clinical signs Neural cell adhesion molecule Li is a multi- observed in a single large Mexican family. Since domain, highly conserved cell surface glyco- then several reports have detailed similar famil- protein expressed primarily on the axons of ies, although they have been described variously developing neurones. It is a member of the as spastic paraplegia type I (SPG1, McKusick immunoglobulin superfamily consisting of six 312900) or clasped thumb-mental retardation domains with core structural motifs similar to syndrome, as well as MASA syndrome. Again those found in immunoglobulins
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