Marden-Walker Syndrome

A number sign (#) is used with this entry because of evidence that Marden-Walker syndrome (MWKS) is caused by heterozygous mutation in the PIEZO2 gene (613629) on chromosome 18p11. One such patient has been reported.

Description

Marden-Walker syndrome is characterized by psychomotor retardation, a mask-like face with blepharophimosis, micrognathia and a high-arched or cleft palate, low-set ears, kyphoscoliosis, and joint contractures. Other features may include Dandy-Walker malformation with hydrocephalus and vertebral abnormalities (summary by Schrander-Stumpel et al., 1993).

There are 2 distal arthrogryposis syndromes with features overlapping those of Marden-Walker syndrome that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 3 (DA3, or Gordon syndrome; 114300) and distal arthrogryposis type 5 (DA5; 108145), which are distinguished by the presence of cleft palate and ocular abnormalities, respectively. McMillin et al. (2014) suggested that the 3 disorders may represent variable expressivity of the same condition.

Clinical Features

Marden and Walker (1966) described an infant with blepharophimosis, micrognathia, immobile facies, kyphoscoliosis, limb contractures, pigeon breast, and arachnodactyly. There was microcystic disease of the kidney. The infant died at 3 months of age. In some respects the case resembled the sibs with myotonic myopathy described by Aberfeld et al. (1965); see 255800.

Fitch et al. (1971) reported a case similar in facial appearance to the case of Marden and Walker (1966). Their patient's severe joint contractures largely disappeared by 6 months of age. Pneumoencephalography showed cerebellar and brainstem hypoplasia. Temtamy et al. (1975) reported identical cases in 2 first-cousin males who in each instance had first-cousin parents.

Howard and Rowlandson (1981) described 2 brothers with blepharophimosis, congenital joint contractures, and mental retardation characteristic of the Marden-Walker syndrome. The mother had 2 other children, both normal, by a different man.

Jaatoul et al. (1982) described a sibship with consanguineous parents and 1 confirmed and 3 probable cases of MWKS.

Gossage et al. (1987) described associated pyloric stenosis and duodenal bands. They summarized the findings in 16 previously reported patients.

Linder et al. (1991) recognized a case in the neonatal period. The infant, whose parents were healthy first cousins of Iranian origin, died at 3 months. They noted that the anterior hairline was very low, meeting the eyebrows. This suggested that abnormalities of the central nervous system had existed before 16 weeks of fetal life. Microscopic changes in the cerebral cortex were seen; on the other hand, light and electron microscopic examinations of the deltoid, iliopsoas, and diaphragmatic muscles were unremarkable as was examination of the heart muscle. Thus, it is difficult to determine why the authors referred to the condition as 'congenital myopathy with oculofacial abnormalities.'

Kotzot and Schinzel (1995) described a severely retarded 23-year-old man with Marden-Walker syndrome. As the patient grew older, the typical facial features became less noticeable. The authors emphasized the behavioral features of aggressiveness and hyperactivity, which became evident at puberty.

Garcia-Alix et al. (1992) described an infant who, in addition to the usual features of blepharophimosis and micrognathia with mild flexion contractures in the elbows, hips, and knees, had absence of primitive reflexes, jerky eye movements, failure to habituate to repeated stimuli, and absence of orientation responses to visual or auditory stimuli. Ultrasonograms and MRI studies of the brain demonstrated absence of corpus callosum, hypoplastic brainstem, and hypoplasia of the inferior vermis and cerebellar hemispheres. Ramer et al. (1993) reviewed the findings in 3 sporadic cases and in 19 previously reported cases. Most of the 19 cases, like their own, had been sporadic, but there were 2 sets of affected sibs and 3 sporadic cases who were products of consanguineous matings. No difference between the sporadic and familial cases was discerned. Differences from the Pena-Shokeir (208150) and Schwartz-Jampel (255800) syndromes were reviewed. Pulmonary hypoplasia was reported only in Pena-Shokeir syndrome and myotonia was present only in individuals with Schwartz-Jampel syndrome.

Schrander-Stumpel et al. (1993) described an isolated case in a boy who, in addition to the usual features, had Dandy-Walker malformation with hydrocephalus and vertebral abnormalities. During pregnancy, there were feeble fetal movements and polyhydramnios. The authors proposed that Marden-Walker syndrome is a cause of the heterogeneous fetal a(hypo)kinesia deformation sequence.

In a 5-month-old daughter of first cousins, Ozkinay et al. (1995) described typical features of the Marden-Walker syndrome; in addition, a Dandy-Walker cyst was identified by MRI scanning.

Renal anomalies are infrequent in Marden-Walker syndrome. Ben-Neriah et al. (1995) made the prenatal diagnosis of MWKS in a fetus with a previously affected sib by finding intrauterine growth retardation and renal cystic disease.

Fryns et al. (1998) presented evidence that Marden-Walker syndrome and isolated distal arthrogryposis (108120) may be variable manifestations of the same entity. They observed the disorder in 2 sibs, the first 2 children of normal, nonconsanguineous parents. The first child, a female, presented with typical Marden-Walker syndrome with Dandy-Walker type CNS malformation, corpus callosum hypoplasia, and enlarged ventricles. In the second pregnancy, echographic examination showed joint contractures of the hands and feet. Examination of the fetus after interruption of the pregnancy at 20.5 weeks of gestation showed a normocephalic male with severe distal arthrogryposis. There was no facial dysmorphism, and pathologic examination of the brain, spinal cord, and muscle was normal. In the case of the first child, facial dysmorphism and typical 'pseudo-trisomy 18' position of the fingers were illustrated. There was camptodactyly of all fingers and fixed adducted position of both thumbs in the palms of the hand, fixed flexion of fingers II-V at the proximal interphalangeal joints, absence of flexion creases at the distal interphalangeal joints, and overriding of fingers II, III, and IV with ulnar deviation.

Cytogenetics

Carrascosa-Romero et al. (2013) reported a girl with manifestations consistent with Marden-Walker syndrome who was found to have a 2.84-Mb deletion at 21q22.11 by array comparative genomic hybridization. Manifestations included intrauterine growth retardation, microcephaly, multiple joint contractures, expressionless face, blepharophimosis, multicystic dysplastic kidney, cerebral dysgenesis, and cognitive impairment. Carrascosa-Romero et al. (2013) reviewed recent reports of cases with total or partial deletions of 22q11.2 in which the genomic size or genes included in the deleted region were well characterized. A high degree of concordance was noted between the clinical features of the Marden-Walker syndrome and those observed in patients with 21q22.11 deletions.

Molecular Genetics

McMillin et al. (2014) sequenced the candidate gene PIEZO2 in 2 probands with Marden-Walker syndrome and identified a de novo missense mutation (R2686C; 613629.0004) in 1 of the patients. The authors noted that a different mutation at the same nucleotide, resulting in an R2686H substitution (613629.0003), had been identified in patients with Gordon syndrome (DA3).