Shuntaro Morikawa

A novel heterozygous mutation of the WFS1 gene leading to constitutive endoplasmic reticulum stress is the cause of Wolfram syndrome

Wolfram syndrome (WS) is a disorder characterized by the association of insulin‐dependent diabetes mellitus (DM), diabetes insipidus, deafness, and optic nerve atrophy. WS is caused by WFS1 mutations encoding WFS1 protein expressed in endoplasmic reticulum (ER). During ER protein synthesis, misfolded and unfolded proteins accumulate, known as “ER stress”. This is attenuated by the unfolded protein response (UPR), which recovers and maintains ER functions. Because WFS1 is a UPR component, mutant WFS1 might cause unresolvable ER stress conditions and cell apoptosis, the major causes underlying WS symptoms. We encountered an 11‐month‐old Japanese female WS patient with insulin‐dependent DM, congenital cataract and severe bilateral hearing loss.

Neonatal screening and a new cause of congenital central hypothyroidism

Congenital central hypothyroidism (C-CH) is a rare disease in which thyroid hormone deficiency is caused by insufficient thyrotropin (TSH) stimulation of a normally-located thyroid gland. Most patients with C-CH have low free thyroxine levels and inappropriately low or normal TSH levels, although a few have slightly elevated TSH levels. Autosomal recessive TSH deficiency and thyrotropin-releasing hormone receptor-inactivating mutations are known to be genetic causes of C-CH presenting in the absence of other syndromes. Recently, deficiency of the immunoglobulin superfamily member 1 (IGSF1) has also been demonstrated to cause C-CH. IGSF1 is a plasma membrane glycoprotein highly expressed in the pituitary. Its physiological role in humans remains unknown. IGSF1 deficiency causes TSH deficiency, leading to hypothyroidism. In addition, approximately 60% of patients also suffer a prolactin deficiency. Moreover, macroorchidism and delayed puberty are characteristic features. Thus, although the precise pathophysiology of IGSF1 deficiency is not established, IGSF1 is considered to be a new factor controlling growth and puberty in children.

Two heterozygous mutations of the AMH gene in a Japanese patient with persistent Müllerian duct syndrome

Abstract Persistent Müllerian duct syndrome (PMDS) is an autosomal recessive disorder of sex development (DSD) characterized by the presence of Müllerian duct derivatives in 46, XY phenotypic males. To date, more than 50 different mutations of the anti-Müllerian hormone gene (AMH) have been reported. Here, we report two novel mutations of AMH in a Japanese patient with PMDS. A 1-year-old male presented with bilateral cryptorchidism and normal male external genitalia. A laparoscopic surgery revealed a uterus and fallopian tubes. Serum AMH was very low. The patient’s elder brother was also diagnosed as having PMDS at another hospital. Genetic analysis of AMH showed two novel mutations of p.N486T and p.V527L. Given that these two amino acids are well conserved among different species of AMH, the substitution of two amino acids might affect the normal function of AMH. In conclusion, PMDS should be included in differential diagnoses of cryptorchidism.

Two Japanese patients with the renal form of pseudohypoaldosteronism type 1 caused by mutations of NR3C2.

Pseudohypoaldosteronism type 1 (PHA1) is a disease characterized by neonatal salt loss due to aldosterone resistance. Two types of PHA1 are known: an autosomal recessive systemic form and an autosomal dominant renal form. The cause of the renal form of PHA1 is heterozygous mutations in NR3C2, which encodes the mineralocorticoid receptor (MR). We encountered two female Japanese infants with the renal form of PHA1 and analyzed NR3C2. The two patients had poor weight gain, and one was developmentally delayed. Genetic analysis identified one novel mutation (c.492_493insTT, p.Met166LeufsX8) and one previously reported mutation (p.R861X). The two produced a premature stop codon, resulting in haploinsufficiency of the MR. In conclusion, genetic analysis of NR3C2 is useful for diagnosis and planning therapeutic strategies.

Spondyloepiphyseal dysplasia congenita caused by double heterozygous mutations in COL2A1

Spondyloepiphyseal dysplasia congenita (SEDC) is a group of rare inherited chondrodysplasias characterized by short stature, abnormal epiphyses, and flattened vertebral bodies. SEDC is usually caused by substitution of glycine residue with another amino acid in the triple helical domains of alpha 1 chains, which consist of type II collagen (COL2A1). Herein, we describe a unique case of SEDC with mild coxa vara (SEDC‐M) caused by double de novo COL2A1 mutations located on the same allele. One mutation, p.G504S, was previously described in patients with SEDC, whereas the other, p.G612A, was a novel mutation; both were located in the triple helical domain. Neither mutation was identified in the parents and appeared to be de novo. To the best of our knowledge, this is the first study involving a patient with a type II collagenopathy with two COL2A1 mutations on the same allele. The case was characterized by a more severe phenotype compared with previously reported cases involving a single p.G504S mutation, which may have been the result of the double mutation.

A Japanese patient with congenital central hypothyroidism caused by a novel IGSF1 mutation

Abstract Background: IGSF1 abnormality causes diverse symptoms, including congenital central hypothyroidism (CCH), prolactin hyposecretion, testicular enlargement and delayed puberty. Case presentation: Here, we report a case of a male patient who visited our hospital with a chief complaint of abdominal pain and short stature, in whom we identified a novel IGSF1 mutation. He was closely examined because of chronic constipation since infancy, persistent abdominal pain at 14 years of age and marked short stature (−4.7 standard deviation [SD] for normal Japanese boys). He was diagnosed with CCH. Decreased prolactin (PRL) secretion was also observed. IGSF1 analysis revealed a novel mutation at the splicing donor site (c.2065+1G>A) in intron 11. In silico analysis predicted this mutation to be a non-functional splice donor site. After thyroid hormone replacement, his thyroid function, constipation and growth rate improved. Conclusions: This is the first report of a patient in whom constipation and short stature led to a diagnosis of CCH with a novel IGSF1 mutation.

A Japanese family with nonautoimmune hyperthyroidism caused by a novel heterozygous thyrotropin receptor gene mutation

Background:Hyperthyroidism caused by activating mutations of the thyrotropin receptor gene (TSHR) is rare in the pediatric population.Methods:We found a Japanese family with hyperthyroidism without autoantibody. DNA sequence analysis of TSHR was undertaken in this family. The functional consequences for the Gs-adenylyl cyclase and Gq/11-phospholipase C signaling pathways and cell surface expression of receptors were determined in vitro using transiently transfected human embryonic kidney 293 cells.Results:We identified a heterozygous mutation (M453R) in exon 10 of TSHR. In this family, this mutation was found in all individuals who exhibited hyperthyroidism. The results showed that this mutation resulted in constitutive activation of the Gs-adenylyl cyclase system. However, this mutation also caused a reduction in the activation capacity of the Gq/11-phospholipase C pathway, compared with the wild type.Conclusion:We demonstrate that the M453R mutation is the cause of nonautoimmune hyperthyroidism.

Two siblings with congenital central hypothyroidism caused by a novel mutation in the IGSF1 gene

Abstract. Genetic defects in the immunoglobulin superfamily member 1(IGSF1) protein are the cause of congenital central hypothyroidism (C-CH). Here we report two Japanese siblings with C-CH due to a novel IGSF1 mutation. The youngest brother showed a failure to thrive, hypothermia, and neonatal icterus six days after birth. Further endocrine evaluations led to the diagnosis of C-CH. In addition, PRL deficiency was later detected. In contrast, the elder brother did not show symptoms of severe hypothyroidism during the neonatal period, but he had been followed up by doctors due to psychomotor developmental delays since the age of 1 yr. At the age of 3 yr, he had low thyroxine and PRL levels and was also diagnosed with C-CH. Because of the C-CH and PRL deficiency, an IGSF1 deficiency was suspected. Sequence analysis of the IGSF1 gene identified a novel hemizygous mutation of p.Trp1173GlyfsTer8 (NM_001170961.1:c.3517del) in both siblings. In conclusion, the phenotypic severity of C-CH is different, even in siblings. Importantly, an IGSF1 deficiency may result in severe hypothyroidism during the neonatal period.

Four Japanese Patients with Congenital Nephrogenic Diabetes Insipidus due to the AVPR2 Mutations

Almost 90% of nephrogenic diabetes insipidus (NDI) is caused by mutations in the arginine vasopressin receptor 2 gene (AVPR2) on the X chromosome. Herein, we reported clinical and biochemical parameters in four cases of three unrelated Japanese families and analyzed the status of the AVPR2. Two of the four patients had poor weight gain. However, in the male and female sibling cases, neither had poor weight gain while toddlers, but in the male sibling, episodes of recurrent fever, polyuria, and polydipsia led to the diagnosis of NDI at 4 years of age. Analysis of AVPR2 identified two nonsense mutations (c.299_300insA; p.K100KfsX91 and c.296G > A; p.W99X) and one missense mutation (c.316C > T; p.R106C). These mutations were previously reported. The patient with c.316C > T; p.R106C had milder symptoms consistent with previous reports. Of the familial cases, the sister was diagnosed as having NDI, but a skewed X-inactivation pattern in her peripheral blood lymphocytes was not identified. In conclusion, our study expands the spectrum of phenotypes and characterized mutations in AVPR2 in NDI.

Clinical features and molecular basis of pseudohypoaldosteronism type 1

Abstract. Pseudohypoaldosteronism (PHA) type 1 is a disease showing mineralocorticoid resistance in the kidney and/or other mineralocorticoid target tissues. Patients with PHA1 present very high plasma aldosterone and renin levels, but they develop excessive salt wasting. There are three types of PHA1. The systemic form of PHA1 is inherited in an autosomal recessive manner and causes severe life-long salt loss in multiple target tissues, such as sweat glands, salivary glands, the colonic epithelium, and the lung. In the systemic form of PHA1, life-long salt supplementation is necessary. The second type is the renal form, where aldosterone resistance is shown only in the kidney, and its inheritance is autosomal dominant. In the renal form of PHA1, salt supplementation generally becomes unnecessary by 1–3 yr of age. The third type is the secondary PHA1, which is strongly associated with urinary tract infections and/or urinary tract malformations. This review summarizes the clinical features and molecular basis of PHA1. Understanding of its pathogenesis can be helpful for the early diagnosis and clinical care of affected children with PHA1.