Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 2

A number sign (#) is used with this entry because multiple congenital anomalies-hypotonia-seizures syndrome-2 (MCAHS2) is caused by mutation in the PIGA gene (311770) on chromosome Xp22.

Description

Multiple congenital anomalies-hypotonia-seizures syndrome-2 is an X-linked recessive neurodevelopmental disorder characterized by dysmorphic features, neonatal hypotonia, myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Some affected individuals die in infancy (summary by Johnston et al., 2012). The phenotype shows clinical variability with regard to severity and extraneurologic features. However, most patients present in infancy with early-onset epileptic encephalopathy associated with developmental arrest and subsequent severe neurologic disability (summary by Belet et al., 2014, Kato et al., 2014). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis.

For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080); for a discussion of genetic heterogeneity of EIEE, see 308350; and for a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Clinical Features

Johnston et al. (2012) reported a family in which 2 brothers had a lethal multiple congenital anomaly disorder. Both infants were born by cesarean section due to breech presentation and were noted to have large size at birth. The first-born boy had Pierre-Robin sequence, a prominent occiput, enlarged fontanel, depressed nasal bridge, short, anteverted nose, malar flattening, upslanted palpebral fissures, overfolded helix, small mouth with downturned corners, and short neck. He had joint contractures, small nails, broad palms with short fingers, and hypotonia. Brain MRI showed thin corpus callosum, white matter immaturity, no septum pellucidum, and cerebellar hypoplasia. Other features included systolic murmur, atrial septal defect, obstructive apnea, vesicoureteral reflux, and a duplicated collecting system. He developed myoclonic seizures with burst-suppression pattern on EEG. He died of pneumonia at age 11 weeks. His brother had similar dysmorphic features, with the addition of a fused metopic suture and high-arched palate. He also had hypotonia, hyperreflexia, contractures, myoclonic seizures, and small patent ductus arteriosus. He died of respiratory failure at age 10 weeks. Postmortem examination showed thin corpus callosum, cerebellar hypoplasia, lack of the olfactory bulb and tracts, abnormal cortical lamination, and dysplastic pons. The diagnosis was hypoxic ischemic encephalopathy and brain malformation with arhinencephaly. Neither patient had evidence of hemolytic anemia or clinical hemoglobinuria, although 1 had low serum calcium and the other had increased serum alkaline phosphatase. A maternal uncle reportedly died of a 'stroke' at age 1 month.

Belet et al. (2014) reported a large Belgian family in which 5 males had profound developmental retardation, axial hypotonia, infantile seizures, and hypsarrhythmia. The family was previously reported as having West syndrome by Claes et al. (1997) (family B). The patients had onset of severe infantile spasms, including myoclonic and generalized seizures, between 5 and 6 months of age. All had complete arrest of psychomotor development after seizure onset, and 4 patients died as children or young adults. Neuropathology of 1 patient showed cortical and cerebellar atrophy, neuronal loss, and gliosis and microspongiosis. Female family members were unaffected.

Kato et al. (2014) reported 5 patients from 4 Japanese families with MCAHS2 manifest as early-onset epileptic encephalopathy. One of the patients had been diagnosed clinically with Schinzel-Giedion syndrome (269150) (Watanabe et al., 2012). Onset of tonic or myoclonic seizures occurred between 1 and 7 months of age, and were refractory in most patients. All had profound intellectual disability, 3 were bedridden with severe motor disturbances, and 2 brothers had a slightly less severe phenotype with no motor disturbances. EEG in the most severe cases showed hypsarrhythmia or burst-suppression pattern. The 3 most severely affected patients had dysmorphic facial features including depressed nasal bridge, short anteverted nose, downturned corners of the mouth, and high-arched palate. Brain MRI of these patients showed cortical atrophy, thin corpus callosum, delayed myelination, and deep white-matter signal abnormalities. One patient had vesicoureteral reflux, 2 had hypotonia, and 2 had joint contractures. Two patients had increased serum alkaline phosphatase. Flow cytometric analysis of patient granulocytes showed decreased expression of the glycosylphosphatidylinositol (GPI)-anchored protein CD16 (see 146740); unaffected carrier mothers showed less severely decreased expression of CD16 on granulocytes.

Van der Crabben et al. (2014) reported a boy with MCAHS2. He had delayed psychomotor development with axial hypotonia and developed refractory seizures at 8.5 months of age. He subsequently showed developmental regression with an encephalopathic phenotype. Other features included atrial septal defect and mild dysmorphic features, such as high anterior hairline, upslanting palpebral fissures, thin vermilion, long philtrum, alveolar ridge overgrowth, and absence of teeth. He also had obesity and accelerated linear growth. Brain MRI showed progressive cerebral atrophy, thin corpus callosum, and insufficient myelination. Laboratory studies showed fluctuating elevated alkaline phosphatase levels. The child died of cardiorespiratory arrest at age 2.5 years.

Terespolsky et al. (1995) reported a family in which 4 maternally related male cousins were born with multiple congenital anomalies. One fetus was voluntarily aborted at 19 weeks' gestation, after multicystic kidneys were detected on ultrasound; the remaining 3 all died within the first 8 weeks of life from pneumonia or sepsis. The 3 liveborn males were hydropic at birth and had a combination of craniofacial anomalies including macrocephaly; apparently low-set posteriorly angulated ears; hypertelorism; short, broad nose with anteverted nares; large mouth with a thin vermilion upper border; prominent philtrum; high-arched or cleft palate; short neck; redundant skin; and hypoplastic nails; skeletal defects involving the upper and lower limbs; and gastrointestinal and genitourinary anomalies. All 3 patients were hypotonic and neurologically impaired from birth. With the exception of a trilobate left lung in 1 patient, the cardiorespiratory system was structurally normal. Terespolsky et al. (1995) suggested that the patients had a severe form of Simpson-Golabi-Behmel syndrome (see SGBS1, 312870). In a follow-up of the affected fetus from the family originally reported by Terespolsky et al. (1995), Fauth et al. (2016) reported that the pregnancy was terminated at 19 weeks' gestation after multiple congenital anomalies were found on prenatal imaging. Fauth et al. (2016) detected a mutation in the PIGA gene in this patient (see MOLECULAR GENETICS).

Fauth et al. (2016) reported 3 male patients from 2 unrelated families with a lethal multiple congenital anomaly syndrome. One died at age 15 days, 1 died at age 3 months, and the third died in utero. A pregnancy in each family was complicated by polyhydramnios, and 2 of the patients had somatic overgrowth. Two patients had severe hypotonia and seizures with a burst-suppression pattern on EEG. Dysmorphic facial features included coarse facies, high anterior hairline, upslanted palpebral fissures, depressed nasal bridge with short nose and anteverted nares, retrognathia, and short webbed neck. Other common features included joint contractures, short limbs, short distal phalanges, and small penis. One patient had a small cerebellum with white matter immaturity and small optic nerves, whereas the other had a smooth gyration pattern. One of the patients had mildly increased serum alkaline phosphatase.

Clinical Variability

Swoboda et al. (2014) reported a 3-generation family in which 3 males had a similar neurodegenerative epileptic encephalopathy inherited in an X-linked recessive pattern. The proband died at age 7 years; his affected brother died at age 16 years; their affected nephew was 15 years old at the time of the report. All patients had normal early development until the onset of recurrent seizures between 7 and 9 months of age. Thereafter, all showed regression of psychomotor development and an encephalopathic phenotype with abnormal movements, myoclonus, spasticity, abnormal eye movements, lack of speech, and profound intellectual disability. All developed deceleration of head growth resulting in microcephaly. Two patients were cortically blind and deaf, and 2 had joint contractures. All 3 patients had hepatomegaly, and 1 died of liver failure at age 16 years. Liver microscopy in this patient showed macro- and micronodular cirrhosis with extensive iron deposition; iron deposition was also found in other internal organs. Neuropathologic examination of this patient showed cortical and cerebellar atrophy, neuronal loss, spongy gliosis, and scant iron deposition in some brain regions. The 15-year-old living patient was profoundly disabled, and serum iron studies suggested increasing systemic iron overload. In addition to the neurologic features, all patients had ichthyosis or seborrheic dermatitis with dryness and desquamation of plaque-like scales. Oral abnormalities included microdontia, widely spaced and pointed teeth, and gingival overgrowth. Swoboda et al. (2014) noted the neurologic overlap with the patients reported by Johnston et al. (2012), but proposed that the disorder in their family be called ferro-cerebro-cutaneous syndrome (FCCS).

Inheritance

The transmission pattern of the disorder in the family reported by Johnston et al. (2012) was consistent with X-linked recessive inheritance.

Mapping

In the family reported by Terespolsky et al. (1995), Brzustowicz et al. (1999) mapped the locus for the disorder to a 6-Mb region on chromosome Xp22 (maximum lod score of 3.31), which they called 'SBGS2' (see 300209). The findings excluded involvement of the glypican-3 gene (GPC3; 300037), which is responsible for SGBS1 and maps to Xq26.

Molecular Genetics

By exome sequencing of the X chromosome in a family with multiple congenital anomalies-hypotonia-seizures syndrome-2, Johnston et al. (2012) identified a germline mutation in the PIGA gene (R412X; 311770.0011). Two affected boys carried the mutation, and 2 obligate female carriers were heterozygous for the mutation; both female carriers showed 100% skewed X inactivation. In vitro functional expression studies in PIGA-null cell lines showed that the R412X mutant protein retained some residual activity with partial restoration of GPI-anchored proteins, suggesting that it is not a null allele. The findings indicated that GPI anchors are important for normal development, particularly of the central nervous system.

In 1 of the patients from the family reported by Claes et al. (1997), Belet et al. (2014) identified a hemizygous truncating mutation in the PIGA gene (311770.0012). The mutation, which was found by X-exome sequencing and confirmed by Sanger sequencing, was not found in 4 healthy males and was present in the unaffected mother of the proband, the unaffected grandmother, and a maternal aunt. DNA was not available from the 4 deceased affected family members.

In 5 boys from 4 unrelated Japanese families with MCAHS2 manifest as early-onset epileptic encephalopathy, Kato et al. (2014) identified hemizygous mutations in the PIGA gene (see, e.g., 311770.0011; 311770.0013-311770.0015). The mutations were found by whole-exome sequencing. In vitro functional expression studies showed a variable loss of PIGA activity, with a correlation between severity of phenotype and degree of residual enzymatic activity.

In 2 affected males from a large family with a variant of MCAHS2, Swoboda et al. (2014) identified a hemizygous in-frame 3-bp deletion in the PIGA gene (leu110del; 311770.0016). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Flow cytometric analysis of the proband's granulocytes showed decreased cell surface levels of some GPI-anchored proteins, although CD59 (107271) expression on red blood cells was normal, suggesting that the mutant protein had some residual activity.

In a boy with MCAHS2, van der Crabben et al. (2014) identified a hemizygous mutation in the PIGA gene (311770.0017).

In 4 male patients from 3 unrelated families with MCAHS2, including the family originally reported by Terespolsky et al. (1995) as Simpson-Golabi-Behmel syndrome (see SGBS2, 300209), Fauth et al. (2016) identified the same hemizygous truncating mutation in the PIGA gene (R412X; 311770.0011). The mutation was found in the heterozygous state in the 2 clinically unaffected mothers who were tested.