Masaaki Yoshimoto

A Case of Neonatal McCune‐Albright Syndrome with Cushing Syndrome and Hyperthyroidism

ABSTRACT. We describe a female newborn infant with McCune‐Albright syndrome. In addition to the cutaneous pigmentation, she had apparent manifestations of hyperthyroidism and Cushing syndrome since birth. X‐ray examinations showed many scattered lucencies in multiple bones. Endocrinological findings were as follows: serum T4 276 nmol/l; free T4 125 pmol/l; TSH <1 mU/l; serum cortisol >2210 nmol/l; plasma ACTH < 10 pg/ml; urinary free cortisol 865 nmol/day; estradiol 0.36 nmol/l. Regardless of treatment with antithyroid drugs and an inhibitor of 3β‐hydroxysteroid dehydrogenase, the patient died of cardiac failure at the age of 4 months. Autopsy findings included a follicle cyst in the right ovary and multinodular hyperplasia in the thyroid and both adrenals. To our knowledge such a severe neonatal form of McCune‐Albright syndrome has not been described in the literature.

Rarity of PIT1 involvement in children from Russia with combined pituitary hormone deficiency

To ascertain the molecular background of combined pituitary hormone deficiency, screening for mutations in the pituitary-specific transcription factor (Pit-1/GHF-1) gene (PIT1) was performed on a cohort of 15 children from Russia with combined growth hormone (GH)/prolactin (Prl)/thyroid-stimulating hormone (TSH) deficiency. The group of patients, suspected of PIT1 mutations, consisted of four familial cases (seven patients) and eight sporadic cases. All had complete GH deficiency and complete or partial Prl and TSH deficiency. Direct sequencing of all six exons of PIT1 and its promoter region showed a C to T transition mutation at codon 14 of exon 1 in a 3 8/12-year-old girl. This novel PIT1 mutation results in a proline to leucine substitution (P14L). The patient was heterozygous for mutant and normal alleles. The heterozygous P14L mutation was also present in her mother as well as in her maternal aunt and grandmother, all of whom were phenotypically normal. There was no mutation in the fathers DNA, suggesting the need for reevaluation of genomic imprinting. In other children of our series, no mutation in PIT1 or in its promotor region was identified. This is the first report on the analysis of PIT1 and its promoter region in Russian children with GH/Prl/TSH deficiency. However, as the involvement of PIT1 mutation is rare in Russia, the other negative cases need to be analyzed for another candidate gene responsible for combined GH/Pr/TSH deficiency.

Mutations in intron 3 of GH-1 gene associated with isolated GH deficiency type II in three Japanese families

Isolated GH deficiency (IGHD) type II is a disorder inherited in an autosomal dominant manner. Three mutations at the donor splice site of intron 3 of the GH‐I gene have been identified in five families. In this report, we describe a novel mutation also at the donor splice site of intron 3 in patients with IGHD type II.

DAX-1 Gene Mutations and Deletions in Japanese Patients with Adrenal Hypoplasia Congenita and Hypogonadotropic Hypogonadism

Abnormality of the DAX-1 gene accounts for many instances of congenital adrenal hypoplasia. In the present study, we performed molecular genetic analysis of DAX-1 in 4 unrelated Japanese patients with adrenal hypoplasia congenita and hypogonadotropic hypogonadism. A double-point mutation for V126M and W171X was identified in 1 family and a complex de novo insertion-deletion mutation was identified in a second. The DAX-1 gene was entirely deleted in a 3rd patient as well as in a 4th with the additional feature of glycerol kinase deficiency.

Rapid detection of a point mutation in thyroid-stimulating hormoneβ-subunit gene causing congenital isolated thyroid-stimulating hormone deficiency

SummaryPrevious study showed that congenital isolated TSH deficiency in Japan is resulted exclusively from a G-A transition at nucleotide 145 in exone 2 of the TSHβ-subunit gene. All reported cases were from the inbred in Shikoku Island. We describe here a 10-year-old boy with hereditary TSH deficiency in the same area. The patient was born with a weight of 3,225 g to non-consanguineous parents. Evaluation at age 2 months revealed typical manifestations of cretinism without goiter. Serum T4, T3, and TSH values were 2.53 μg/dl, 107 ng/dl, and 0.5 μU/ml, respectively. A TRH stimulation test showed no increment of serum TSH value. Other anterior pituitary hormone levels were all within the normal range. Two oligonucleotide primers T1a and T1b were synthesized according to the sequence data. Amplified 169 bp nucleotides in exon 2 of the TSHβ gene with this primer set were digested with MaeI. Both the phenotypically normal brother and normal controls showed only the 169 bp fragment, whereas the proband showed 140 and 29 bp fragments and both parents showed three fragments; 169, 140, and 29 bp. These results were consistent with the point mutation of TSHβ gene in Japanese patients with congenital isolated TSH deficiency. Our PCR method with MaeI digestion contributes to the rapid detection of the homozygous patient and the heterozygous carrier.

Pubertal Changes in Testicular 3β-Hydroxysteroid Dehydrogenase Activity in a Male with Classical 3β-Hydroxysteroid Dehydrogenase Deficiency Showing Spontaneous Secondary Sexual Maturation

Males with classical 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency manifest appropriate secondary sexual maturation with an elevation in serum testosterone levels at pubertal age. To define the origin of serum testosterone, we evaluated a male patient with classical 3 beta-HSD who showed pubertal development. High values of testosterone and a ratio of delta(5) to delta(4) steroids in the spermatic vein indicated direct production of considerable amounts of testosterone and a persistent defect of 3 beta-HSD activity in the gonad. Immunohistochemical analysis showed distinct immunoreactivity in the Leydig cells of the patient. The patient was homozygous for a nonsense mutation in the type-II 3 beta-HSD gene. We propose that gonadal type-I 3 beta-HSD could be expressed by gonadotropin stimulation at pubertal age, and delta(4)-steroid precursors would convert to testosterone.

A Case of Severe Pituitary Dwarfism Associated with Prolactin and Thyroid Stimulating Hormone Deficiencies

ABSTRACT. An extreme dwarf 10‐year‐old boy was described. His clinical features resemble those of isolated GH deficiency type 1A, but the Southern blot analysis showed no gross deletion in the GH structural gene. Endocrinological evaluations showed severe GH and PRL deficiencies, and mild TSH deficiency. The simultaneous deficiencies of anterior pituitary hormones in our patient resemble those of the Snell and Ames dwarf mice and suggest a common etiology. The evolutionary and embryological similarities between GH and PRL imply that mutations at a gene which controls GH and PRL production in somatotropes and lactotropes or at a gene of which product affects the embryological development from a common ancestral cell in the anterior pituitary gland may be a primary defect in our patient.

Prenatal DNA analysis in four embryos/fetuses at risk of 21-hydroxylase deficiency

Prentatal diagnosis of 21-hydroxylase deficiency (21-OHD) in two unrelated embryos and two fetuses was attempted with the Southern hybridization method using the 21-hydroxylase (21-OHase) complementary DNA as a probe. The two embryos whose genomic DNA was extracted from their chorionic vili both had four TaqI fragments (3.7 kb, 3.2 kb, 2.4 kb and 2.3 kb) identical to those of their respective parents and normal controls, while the DNA from each proband of these two families lacked with the 3.7 kb and the 2.3 kb fragments corresponding to the functional 21-OHase gene (21-OHase B gene). These findings indicated that none of the embryos examined were deletion homozygotes for the 21-OHase B gene. In the two fetuses, only amniotic fluid cells were available for prenatal diagnosis. The results of Southern hybridization analysis were uninformative since all family members, including the probands and fetuses, had all four TaqI fragments. Linkage studies between 21-OHD and human leukocyte antigen (HLA) haplotypes and those between the disease and restriction fragment length polymorphisms of the 4th complement gene revealed that the fetus of one family was normal. The other fetus could not be diagnosed because a recombination between the class I HLA and the 21-OHD loci had occurred in this family.

Neonatal onset of medium-chain Acyl-CoA dehydrogenase deficiency in two siblings

Two male siblings with medium-chain acyl-CoA dehydrogenase deficiency were reported, in whom the enzyme activity was essentially undetectable and the symptoms and signs, including cyanosis, apnea, low body temperature, hypoglycemia and hyperammonemia, appeared within 48 hours of life. Muscle weakness and cardiomegaly in association with morphological abnormalities of mitochondria in skeletal and cardiac muscles, respectively, were found on electron microscopic examination in one of them. These observations suggest that the patients suffered from the most severe form of the disease, which has not been described in the literature.

Newly recognized syndrome of metaphyseal undermodeling, spondylar dysplasia, and overgrowth: Report of two adolescents and a child

We report on a previously undescribed syndrome characterized by generalized skeletal alterations and overgrowth in three unrelated individuals: a boy who died at age 16 years, a 16‐year‐old girl, and a 15‐month‐old boy. The skeletal changes included bony overgrowth of the skull base, spondylar dysplasia, and undermodeling of the tubular bones. Bone age was accelerated in early childhood. Overgrowth, which was independent of GH–IGF axis, was of prenatal onset in the two boys, but postnatal in the girl. In the two adolescents, growth rate did not decline with age, and high‐dose estrogen therapy failed to induce physeal fusion. Their adolescent height reached +4∼+7 SD of the mean. Delayed puberty in the girl and cryptorchidism and hypospadias in the younger boy raised the possibility that hypogonadism is a syndromic constituent. Molecular analysis of IGF2, GPC3, and FGFR3 in the older boy yielded no abnormalities.