Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 1

A number sign (#) is used with this entry because multiple congenital anomalies-hypotonia-seizures syndrome-1 (MCAHS1) is caused by homozygous mutation in the PIGN gene (606097) on chromosome 18q21.

Description

Multiple congenital anomalies-hypotonia-seizures syndrome is an autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. Most affected individuals die before 3 years of age (summary by Maydan et al., 2011). The disorder is caused by a defect in glycosylphosphatidylinositol biosynthesis; see GPIBD1 (610293).

Genetic Heterogeneity of Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome

MCAHS2 (300868) is caused by mutation in the PIGA gene (311770) on chromosome Xp22, and MCAHS3 (615398) is caused by mutation in the PIGT gene (610272) on chromosome 20q13.

Knaus et al. (2018) provided a review of the main clinical features of the different types of MCAHS, noting that patients with mutations in the PIGN, PIGA, and PIGT genes have distinct patterns of facial anomalies that can be detected by computer-assisted comparison. Some individuals with MCAHS may have variable increases in alkaline phosphatase (AP) as well as variable decreases in GPI-linked proteins that can be detected by flow cytometry. However, there was no clear correlation between AP levels or GPI-linked protein abnormalities and degree of neurologic involvement, mutation class, or gene involved. Knaus et al. (2018) concluded that a distinction between MCAHS and HPMRS1 (239300), which is also caused by mutation in genes involved in GPI biosynthesis, may be artificial and even inaccurate, and that all these disorders should be considered and classified together under the more encompassing term of 'GPI biosynthesis defects' (GPIBD).

Clinical Features

Maydan et al. (2011) reported 7 patients from a large consanguineous Arab Israeli kindred with a syndrome characterized by severe neurologic impairment, lack of development, seizures, and multiple congenital anomalies resulting in early death. Most of the affected individuals were born with increased birth weight and a large head circumference. There were variable dysmorphic features, including open mouth, thin lips, depressed nasal bridge, bitemporal narrowing, large ears with overfolded helices, and coarse facies. Most had nystagmus or wandering eyes. Five had cardiovascular defects, such as patent foramen ovale or patent ductus arteriosus; 2 had atrial septal defects. Three had urinary tract anomalies, including hydrocele, hydronephrosis, and a trabecular urinary bladder. Gastrointestinal abnormalities included gastroesophageal reflux (in 3), anal stenosis (1), and imperforate anus (1). Deep plantar grooves were also noted. All had severe neonatal hypotonia, and 6 had seizures. Developmental milestones were absent. Other neurologic signs included hyporeflexia (in 5), tremor (5), hoarse cry (4), hyperreflexia (2), and choreoathetosis (2). Brain imaging of 2 patients showed no major structural abnormalities, but 1 had delayed maturation of the white matter and thin corpus callosum. All but 1 died before the age of 3.3 years; 1 patient was still alive at the age of 29 months. There was no clinical evidence of thrombosis.

Ohba et al. (2014) reported 2 Japanese sibs with MCAHS1. A 9-year-old girl showed vertical nystagmus without eye pursuit at age 1 month. She had hypotonia and severely delayed psychomotor development since infancy, and she developed complex partial seizures at age 8 months. Dysmorphic features included prominent occiput, bitemporal narrowing, epicanthal folds, open mouth, tented upper lip, high-arched palate, and micrognathia. Brain MRI at age 6 months was normal, but later showed cerebellar atrophy and delayed myelination. She also had vesicoureteral reflux. Her 2-year-old younger brother was similarly affected, except that his brain MRI was normal at age 2 months.

Nakagawa et al. (2016) reported a 6-year-old Japanese boy, born of unrelated parents, with MCAHS1. He had hypotonia from early infancy, developed seizures and nystagmus at age 3 months, and had severely delayed development with no meaningful speech. Dysmorphic features included frontal bossing, hypertelorism, low-set ears, high nasal bridge, anteverted nares, and downturned open mouth. Other features included small feet and fingers, refractory epilepsy, apneic spells, and cerebellar atrophy. Serum alkaline phosphatase levels were normal, but granulocytes showed decreased expression of GPI-anchored proteins.

Fleming et al. (2016) reported 4 patients from 3 unrelated families with MCAHS1 confirmed by genetic analysis. Three of the patients, including 2 sibs, developed intractable and severe seizures in the first few months of life. The fourth patient had a slightly less severe phenotype and developed intractable seizures at age 11 years after a history of global developmental delay. All patients had delayed psychomotor development and intellectual disability, although the youngest and most severely affected patient was only 4 months old. Additional abnormal neurologic signs observed in the patients included axial hypotonia, limb hypertonia and spasticity, hyperreflexia, roving eye movements, and nystagmus. Dysmorphic features included coarse facial features, bitemporal narrowing, micrognathia, high-arched palate, low-set, posteriorly rotated, or cupped ears, and depressed nasal bridge. Three patients had severe gastroesophageal reflux disease, 2 had narrow or pointed inferior ilia, and the 4-month-old had multiple abnormalities of the distal phalanges. Brain imaging was normal in the 2 sibs, but showed cerebral atrophy in the other 2 patients. One patient died at age 2 years and another died at age 14 years. Three patients did not have visceral abnormalities; only the most severely affected patient, the 4-month-old, had resolving splenomegaly and hydronephrosis. This patient also had abnormalities in the globi pallidi, midbrain, and corticospinal tract on brain imaging. There was some evidence for a genotype/phenotype correlation in that the patient with 2 missense mutations in the PIGN gene had a slightly less severe phenotype than the infant with 2 loss-of-function mutations. Exome sequencing identified biallelic mutations affecting the PIGN gene in all patients. The mutations segregated with the disorder in the families and were rare in public databases, but functional studies were not performed. The 2 sibs and the less severely affected patient carried variants in other genes as well. The report expanded the phenotype associated with PIGN mutations, and suggested that multiple congenital anomalies are not necessarily core features of the disorder, whereas intractable epilepsy is.

Khayat et al. (2016) reported a 6-year-old girl, born of consanguineous Israeli Arab parents, with MCAHS1. She was a hypotonic infant who developed seizures at age 6 months and was later noted to have severely delayed psychomotor development. Brain imaging initially showed enlarged ventricles, suggesting brain atrophy, and later showed progressive white matter disease. Dysmorphic features included brachycephaly, flat face, upslanting palpebral fissures, epicanthal folds, synophrys, small nose and mouth, small and abnormally shaped ears, and short neck. She also had nystagmus, increased peripheral tone, mild hypoplasia of the distal fingers, gastroesophageal reflux, and some hypopigmented macules. At age 5, she had refractory epilepsy, was not ambulant, and had no speech. Family history was significant for 2 previous spontaneous abortions and a brother of the proband who died of congenital diaphragmatic hernia at age 12 days.

Clinical Variability

McInerney-Leo et al. (2016) reported a nonconsanguineous couple of northern European descent who had 2 pregnancies in which the fetus was affected with multiple congenital anomalies detected by prenatal ultrasound. Both affected fetuses had congenital diaphragmatic hernia, cleft lip, cystic and mildly echogenic kidneys, and pulmonary hypoplasia. Based on these findings, both fetuses were diagnosed clinically with Fryns syndrome (FRNS; 229850). The pregnancies were terminated and postmortem examination was not performed. An unrelated fetus with similar features of Fryns syndrome was born to an Iraqi couple with a history of 3 first-trimester miscarriages. Prenatal imaging and postmortem examination showed cystic hygroma, echogenic kidneys, multiple cardiac defects, congenital diaphragmatic hernia, exomphalos, short distal phalanges, distal and dysmorphic facial features, including hypertelorism, low-set ears, anteverted nares, flat nasal bridge, long philtrum, macrostomia, and cleft palate. Whole-exome sequencing identified biallelic truncating mutations in the PIGN gene (606097.0009-606097.0011) in all 3 fetuses that segregated with the disorder in the families. Two additional unrelated patients, including a fetus, with a clinical diagnosis of Fryns syndrome did not carry PIGN mutations.

Inheritance

The transmission pattern of multiple congenital anomalies-hypotonia-seizures syndrome in the family reported by Maydan et al. (2011) was consistent with autosomal recessive inheritance.

Molecular Genetics

By homozygosity mapping followed by candidate gene sequencing in affected members of a consanguineous Arab Israeli family with multiple congenital anomalies and neurologic impairment, Maydan et al. (2011) identified a homozygous mutation in the PIGN gene (R709Q; 606097.0001).

In 2 Japanese sibs with severely delayed psychomotor development, hypotonia, nystagmus, seizures, and dysmorphic features, Ohba et al. (2014) identified compound heterozygous mutations in the PIGN gene (606097.0002 and 606097.0003). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient granulocytes showed 26 to 54% levels of GPI-anchored proteins CD16 (see 146740) and CD24 (600074). Transient expression of the mutations in PIGN-null HEK293 cells showed decreased expression of CD59 (107271), consistent with severe or complete loss of PIGN activity.

In a 6-year-old girl, born of consanguineous Israeli Arab parents, with MCAHS1, Khayat et al. (2016) identified a homozygous missense mutation in the PIGN gene (D252V; 606097.0004). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient granulocytes showed significantly decreased expression of GPI-anchored proteins CD24 (600074) and CD18 (600065) compared to controls, suggesting that the mutation was deleterious to PIGN function.

In 2 sisters with MCAHS1, Fleming et al. (2016) identified compound heterozygosity for a truncating and a splice site mutation in the PIGN gene (606097.0005 and 606097.0006). An unrelated patient with a less severe phenotype was compound heterozygous for 2 missense variants in the PIGN gene. In addition, a severely affected infant was compound heterozygous for a frameshift mutation (606097.0007) and an intragenic deletion (606097.0008), predicted to result in a complete loss of PIGN. The findings suggested a genotype/phenotype correlation with truncating or loss-of-function mutations resulting in a more severe phenotype compared to missense mutations. Functional studies of the variants were not performed.