Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 3

A number sign (#) is used with this entry because of evidence that multiple congenital anomalies-hypotonia-seizures syndrome-3 (MCAHS3) is caused by homozygous or compound heterozygous mutation in the PIGT gene (610272) on chromosome 20q13.

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 (GPI) biosynthesis.

For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080).

For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Clinical Features

Kvarnung et al. (2013) reported a consanguineous family of Turkish origin in which 4 patients had severe intellectual and motor disability and multiple congenital anomalies. The patients were born with mild macrosomia and macrocephaly and showed hypotonia and delayed psychomotor development from an early age. Dysmorphic features included brachycephaly, high forehead with bitemporal narrowing, depressed nasal bridge, long philtrum with a deep groove, and open mouth due to hypotonia. Brain imaging showed variable abnormalities, including frontotemporal atrophy, cerebellar hypoplasia, and primitive Sylvian fissures, suggesting a possible neuronal migration defect. All patients developed seizures of various type before age 2 years. Ophthalmologic findings included poor vision, strabismus, nystagmus, and hyperopia. Tooth abnormalities included premature loss of incisors, and renal abnormalities included nephrocalcinosis and ureteral dilation; 1 patient had renal cysts. All patients also had some type of skeletal findings, including scoliosis, pectus excavatum, short upper extremities, slender and osteopenic long bones with large secondary ossification centers, wide and long femoral necks, and delayed bone age. Other features included inverted nipples and restrictive cardiomyopathy. Laboratory studies showed decreased alkaline phosphatase, increased serum calcium, and hypercalciuria.

Nakashima et al. (2014) reported a Japanese girl with MCAHS3. She showed poor feeding soon after birth and presented at age 4 months with tonic seizures with apnea and myoclonic seizures. The seizures were refractory to most medications, and she had repeated episodes of convulsive status epilepticus induced by infection. Other features included hypotonia, unstable head control, strabismus, nystagmus, cerebral visual impairment, patent ductus arteriosus, and left hydronephroureter with ureteral stenosis. She also had dysmorphic features, including low-set ears, micrognathia, malar flattening, upslanting palpebral fissures, depressed nasal bridge with anteverted nares, downturned corners of the mouth, tented lip, and high-arched palate. Brain imaging showed progressive cerebral, cerebellar, and brainstem atrophy, and EEG showed low-amplitude irregular background activity and spike-and-slow wave epileptic discharges. Radiographs showed neurogenic arthrogryposis and osteoporosis. Laboratory studies showed decreased serum alkaline phosphatase with normal calcium. At age 12 years, she had profound psychomotor retardation and was bedridden with absent speech.

Lam et al. (2015) described 2 children with MCAHS3, born of nonconsanguineous parents of mixed African American and Caucasian background. The sister and brother, aged 7 and 6, had hypotonia and severe global developmental delay and intractable seizures along with endocrine, ophthalmologic, skeletal, hearing, and cardiac anomalies. Both were born at 31 weeks' gestation and were cared for in the neonatal intensive care unit for approximately 6 weeks with cardiorespiratory and feeding support. Both experienced onset of seizures at 5 weeks of age; seizures progressed to poorly controlled myoclonic, tonic, and tonic-clonic that occasionally generalized. Strabismus and nystagmus were present in both. Echocardiogram in the girl showed patent foramen ovale and small muscular ventricular septal defect, and in the boy showed dilated right atrium and atrial septal defect with left to right shunt, which was treated with an Amplatzer device at 25 months of age. MRI showed progressive cerebellar and cerebral atrophy. Lam et al. (2015) noted that their patients differed from patients in previous reports in bone and endocrine features; their patients had normal to advanced bone age and normal alkaline phosphatase, plasma calcium, plasma phosphate, urine calcium, and parathyroid hormone values.

Skauli et al. (2016) described 2 brothers, born to first-cousin parents of Somali origin, with features of MCAHS3. In addition to findings typically seen in patients with MCAHS3, the brothers had pyramidal tract neurologic signs including spasticity of the lower limbs, increased lower limb reflexes, bilateral ankle clonus, and Babinski sign. In contrast to previously reported patients, they did not have skeletal, cardiac, or genitourinary anomalies.

Kohashi et al. (2018) reported an 11-month-old boy who was born to healthy, nonconsanguineous Japanese parents. He presented with distinctive external features, including micrognathia, high-arched eyebrows, epicanthus, telecanthus, depressed nasal bridge, short anteverted nose, long philtrum, tented lip, and high-arched palate. He had skeletal abnormalities including pectus excavatum, clinodactyly, middle phalanx defect, and delayed bone age. Urogenital abnormalities included nephrocalcinosis, cryptorchidism, and perineal groove. He also had duplication of the esophagus. There were no cardiovascular abnormalities. He developed epileptic apnea at 2 months of age that was successfully controlled with valproic acid; however, epileptic apnea recurred with additional tonic and myoclonic seizures at 8 months of age. The patient exhibited psychomotor regression and increased frequency of epileptic apnea during sleep. Seizures were refractory to 3 antiepileptics. At 11 months he was bedridden, in a frog-like position, and could move only his arms and feet in response to noxious stimuli. Height and weight were normal. Alkaline phosphatase was extremely low. Seizures were intractable and required hospitalization for 6 months. Acetazolamide was effective for the treatment of the epileptic apnea. Kohashi et al. (2018) reviewed previously reported patients with MCAHS3, all of whom shared profound intellectual disability, hypotonia, skeletal anomalies, ophthalmologic problems, global cerebral and cerebellar atrophy, and seizures. Cardiologic, gastrointestinal, and urologic manifestations were variable.

Inheritance

The transmission pattern of MCAHS3 in the family reported by Kvarnung et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 affected members of a consanguineous Turkish family with multiple congenital anomalies-hypotonia-seizures syndrome-3, Kvarnung et al. (2013) identified a homozygous mutation in the PIGT gene (T183P; 610272.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in several large control databases, including 6,500 Exome Sequencing Project exomes and the 1000 Genomes Project, or in 200 Danish exomes. Flow cytometric analysis of patient granulocytes and monocytes showed decreased amounts of GPI-anchored proteins CD16B (610665) and CD59 (107271) compared to controls, indicating that the mutation results in impaired membrane anchoring of GPI-linked proteins. The T183P variant was unable to rescue gastrulation defects of morpholino-knockout zebrafish, consistent with a defect in enzyme function.

In a Japanese girl with MCAHS3, Nakashima et al. (2014) identified compound heterozygous mutations in the PIGT gene (E84X, 610272.0003 and R488W, 610272.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient granulocytes showed decreased surface expression of certain GPI-anchored proteins. Transfection of the mutations into PIGT-deficient CHO cells showed that the R488W mutation could partially restore surface expression of GPI-anchored proteins, whereas the E84X mutation resulted in a complete loss of function.

In 2 brothers with features of MCAHS3, who were born to first-cousin parents of Somali origin, Skauli et al. (2016) identified a homozygous mutation in the PIGT gene (G360V; 610272.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not seen in the 1000 Genomes or ExAC databases or in an in-house database of 443 exomes of mixed ethnicity. The mutation alters a highly conserved amino acid located in the GPI-transamidase domain, which transfers mature GPI anchors to target proteins. In vitro studies in cells from the 2 brothers showed reduced levels of GPI anchors and GPI-anchored proteins on the cell surface.

In 2 sibs with MCAHS3, Lam et al. (2015) reported compound heterozygosity for a missense mutation (R488W; 610272.0004) and a frameshift mutation (610272.0006).

Kohashi et al. (2018) reported an 11-month-old boy with acetazolamide-responsive epileptic apnea who presented with decreased serum alkaline phosphatase associated with compound heterozygous PIGT mutations, glu84 to ter (E84X; 610272.0003) and a novel missense variant, gly366 to trp (G366W; 610272.0007).