Noritaka Furuya

Further delineation of 9q22 deletion syndrome associated with basal cell nevus (Gorlin) syndrome : Report of two cases and review of the literature

Basal cell nevus syndrome (BCNS; Gorlin syndrome) is an autosomal dominant disorder, characterized by a predisposition to neoplasms and developmental abnormalities. BCNS is caused by mutations in the human homolog of the Drosophila patched gene‐1, PTCH1, which is mapped on chromosome 9q22.3. Nonsense, frameshift, in‐frame deletions, splice‐site, and missense mutations have been found in the syndrome. Haploinsufficiency of PTCH1, which is caused by interstitial deletion of 9q22.3, is also responsible for the syndrome. To date, 19 cases with interstitial deletion of long arm of chromosome 9 involving the region of q22 have been reported. We describe two unrelated patients with some typical features of BCNS associated with deletion of 9q21.33‐q31.1 and determined the boundary of the deletion by fluorescence in situ hybridization (FISH) with bacterial artificial chromosome (BAC) clones. The results showed that the size of deletions is between 15.33 and 16.04 Mb in patient 1 and between 18.08 and 18.54 Mb in patient 2. Although the size and breakpoints were different from those of previously reported cases, the clinical features are common to patients with 9q22 deletion associated with BCNS. Delineation of the 9q22 deletions and further consideration of the genes responsible for the characteristic manifestations may provide insight into this newly recognized deletion syndrome.

1p36 deletion syndrome associated with Prader-Willi-like phenotype.

Background:  1p36 deletion syndrome is one of the most common subtelomeric deletion syndromes, characterized by moderate to severe mental retardation, characteristic facial appearance, hypotonia, obesity, and seizures. The clinical features often overlap with those of Prader–Willi syndrome (PWS). To elucidate the phenotype–genotype correlation in 1p36 deletion syndrome, two cases involving a PWS‐like phenotype were analyzed on molecular cytogenetics.

5,10-Methylenetetrahydrofolate reductase deficiency with progressive polyneuropathy in an infant.

5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency is the most prevalent inborn error of folate metabolism, and has variable clinical manifestations from asymptomatic to severe psychomotor retardation, microcephalus and seizure. In untreated infantile cases, it predominantly affects the central nervous system, which is sometimes fatal. On the other hand, peripheral nerve involvement is uncommon. We present a severe infantile case of MTHFR deficiency that manifested unilateral phrenic nerve palsy with communicating hydrocephalus, developmental delay and died at 11months of age. An enzymatic study confirmed MTHFR deficiency with residual activity of 0.75% of mean control values in cultured fibroblasts. Mutation analysis of the MTHFR gene revealed homozygous, tandem missense mutations c.[446G>T; 447C>T] in exon 3 of the MTHFR gene converting glycine to valine (Gly149Val). In MTHFR deficiency, betaine may improve the symptoms if started immediately after birth by reducing the level of serum homocysteine and increasing that of methionine. Our results show that we should be aware of possible inborn errors of folate metabolism such as MTHFR deficiency, in infants with unexplained developmental delay manifesting rapidly progressive polyneuropathy.

Pure duplication of 19p13.3

Chromosomal abnormalities involving 19p13.3 have rarely been described in the published literature. Here, we report on a girl with a pure terminal duplication of 6.1 Mb on 19p13.3, caused by an unbalanced translocation der(19)t(10;19)(qter;p13.3)dn. Her phenotype included severe psychomotor developmental delay, skeletal malformations, and a distinctive facial appearance, similar to that of a patient previously reported by Lybaek et al. [Lybaek et al. (2009); Eur J Hum Genet 17:904–910]. These results suggest that a duplication of >3 Mb at the terminus of 19p13.3 might represent a distinct chromosomal syndrome.

Fetal outcome of trisomy 18 diagnosed after 22 weeks of gestation: Experience of 123 cases at a single perinatal center

To investigate the pregnancy outcome of the fetuses with trisomy 18, we studied 123 cases of trisomy 18 who were born at our hospital from 1993 to 2009. Among them, 95.9% were diagnosed with trisomy 18 prenatally. Prenatal ultrasound findings showed fetal growth restriction in 77.2%, polyhydramnios in 63.4% and congenital heart defects in 95.1%. For 18 cases, cesarean section (C‐section) was chosen, and for 75 cases, transvaginal delivery was chosen. Premature delivery occurred in 35.5%. Stillbirths occurred in 50 cases (40.7%). Fetal demise before onset of labor occurred in 30 cases and fetal demise during labor occurred in 20 cases which was 26.7% of vaginal deliveries. Among the 73 live‐born infants, the survival rate for 24 h, 1 week, 1 month and 1 year were 63%, 43%, 33% and 3%. The median survival time was 3.5 days. There was no significant difference between the survival time of C‐section and that of vaginal delivery. However, for the births involving breech presentation, the survival time of C‐section was significantly longer than that of vaginal delivery. When the fetus is diagnosed with trisomy 18, the parents have to make many choices. These findings constitute critical information in prenatal counseling to the couples whose fetuses have been found to have trisomy 18, especially when they choose palliative approaches in the perinatal management.

Expression analysis of a 17p terminal deletion, including YWHAE, but not PAFAH1B1, associated with normal brain structure on MRI in a young girl†

Tyrosine 3‐monooxygenase/tryptophan 5‐monooxygenase activation protein, epsilon polypeptide (YWHAE), on chromosome 17p13.3, has been shown to play a crucial role in neuronal development. The deletion of YWHAE, but not platelet‐activating factor acetylhydrolase, isoform 1b, subunit 1 (PAFAH1B1), underlies a newly recognized neurodevelopmental disorder, characterized by significant growth retardation, developmental delay/intellectual disability (DD/ID), distinctive facial appearance, and brain abnormalities. Here, we report on a girl with a terminal deletion of 17p13.3, including YWHAE but not PAFAH1B1, showing normal brain structure on MRI. She had mild developmental delay, a distinctive facial appearance, and severe growth retardation despite normal growth hormone levels, which was improved by growth hormone therapy. Expression analysis of YWHAE and PAFAH1B1 yielded results consistent with array CGH and FISH results. These results indicate that the dosage effect of YWHAE varies from severe to very mild structural brain abnormalities, and suggest that the expression of YWHAE is associated with a complex mechanism of neuronal development.

Hemoglobin Seattle detection based on low capillary oxygen saturation: First reported case in Japan

Peripheral capillary oxygen saturation (SpO2), or pulse oximetry, is commonly used in modern medical practice as a basic vital index of health. Although low SpO2 is generally caused by pulmonary, cardiac, or vascular disease, hemoglobin (Hb) abnormalities can also cause reduced pulse oximetry. Hb alterations, however, are sometimes overlooked as the cause of low SpO2, especially when they are congenital. Hemoglobin Seattle (Hb-Seattle) is an inheritable hemoglobinopathy that involves the substitution of aspartic acid for alanine at codon 70 of the b-globin chain, a side chain of which is located in the heme contact region of the protein. Because mutations in this region could affect molecular stabilization and oxygen affinity, patients with this variant have hemolytic chronic anemia and hypoxia symptoms. Since it was first identified in 1970, Hb-Seattle has been reported in three families, with a total of nine individuals reported to date (Table S1). We herein describe the first reported case of Hb-Seattle in Japan, the diagnosis of which was prompted by low SpO2. A 13-year-old Japanese girl was referred to Saitama Citizens Medical Center because of normocytic anemia and low SpO2. She was incidentally diagnosed with anemia at the age of 12 at a local clinic. The parent reported that the patient had displayed facial pallor intermittently since early childhood. Her father, who had died of renal cancer, had a history of pediatric anemia of undetermined etiology persisting into adulthood. The patient was ethnically pure Japanese and had no other family history of hematological disease. Although she was otherwise in good health on admission, the patient had facial pallor with anemic palpebral conjunctiva. Although SpO2 was 89%, no intolerance to physical exercise was observed. No jaundice, hepatomegaly, or splenomegaly was observed. Laboratory test indicated normocytic normochromic anemia with hemolysis: Hb, 8.9 g/dL; mean corpuscular volume, 90.7 fL; reticulocyte count, 3.25%; serum haptoglobin, 8 mg/dL (reference range, 19–170 mg/dL); and fetal Hb (HbF), 2.7% (reference range, 0–1.7%). Congenital cyanotic heart disease and respiratory disease were ruled out based on imaging and physical examinations. Peripheral blood smear showed target cells (Fig. 1a) and inclusion bodies in red blood

Familial severe congenital diaphragmatic hernia: Left herniation in one sibling and bilateral herniation in another

Familial congenital diaphragmatic hernia (CDH) is extremely rare; it comprises about 2% of all CDH cases. The empirical risk is about 2%, increasing to 10% in a family with two affected children. This report describes severe CDH in two siblings who had been diagnosed prenatally. The female newborn diagnosed with left CDH prenatally was born at 38 weeks of gestation. Despite surgical repair and intensive treatment, she died 10 days after birth. Her younger brother was born at 39 weeks of gestation after being diagnosed with bilateral CDH prenatally, and died 75 min after birth. Both infants had neither other congenital anomaly nor chromosomal abnormalities. Their parents are healthy without consanguinity. Their first daughter and the fourth child have no congenital anomalies.

Spastic quadriplegia in Down syndrome with congenital duodenal stenosis/atresia.

Down syndrome is an autosomal chromosome disorder, characterized by intellectual disability and muscle hypotonia. Muscle hypotonia is observed from neonates to adulthood in Down syndrome patients, but muscle hypertonicity is extremely unusual in this syndrome. During a study period of nine years, we found three patients with severe spastic quadriplegia among 20 cases with Down syndrome and congenital duodenal stenosis/atresia (3/20). However, we could find no patient with spastic quadriplegia among 644 cases with Down syndrome without congenital duodenal stenosis/atresia during the same period (0/644, P < 0.05). Further, we did not find any cases with spastic quadriplegia among 17 patients with congenital duodenal stenosis/atresia without Down syndrome admitted during the same period to use as a control group (0/17, P < 0.05). Our results suggest that congenital duodenal stenosis/atresia is a potential risk factor for spastic quadriplegia in patients with Down syndrome. Long‐term survival is improving, and the large majority of people with Down syndrome are expected to live well into adult life. Management and further study for the various problems, representing a low prevalence but serious and specific to patients with Down syndrome, are required to improve their quality of life.