A case of syndromic congenital hypothyroidism with a 15.2 Mb interstitial deletion on 2q12.3q14.2 involving PAX8.

Paired box 8 (PAX8) mutations are an established genetic cause of congenital hypothyroidism (CH). The majority of these mutations are found in the protein-coding exons of the gene. The proband, a 3-yr-old girl, had tetralogy of Fallot and polydactyly soon after birth. She was diagnosed with CH in the newborn screening for CH. She had a high serum TSH level (239 mU/L) and low free T4 level (0.7 ng/dL). Ultrasonography revealed thyroid hypoplasia. We performed array comparative genomic hybridization because the patient exhibited a variety of symptoms across multiple organ systems. The analysis revealed a novel heterozygous deletion that spanned a 15.2 Mb region in 2q12.3q14.3 (GRCh37; chr2:109,568,260-124,779,449). There were 71 protein-coding genes in this region, including two genes (PAX8 and GLI2) associated with congenital endocrine disorders. The common clinical features of the two previously reported patients with a total PAX8 deletion and our case were CH, short stature and intellectual disability, but the severity of hypothyroidism and other clinical features were variable. In conclusion, we describe a syndromic CH patient with a novel 2q12.3q14.3 deletion involving PAX8. Patients with CH, whose unifying diagnosis is not obvious, could have a genomic deletion involving PAX8.

A hypomorphic variant in the translocase of the outer mitochondrial membrane complex subunit TOMM7 causes short stature and developmental delay.

Mitochondrial diseases are a heterogeneous group of genetic disorders caused by pathogenic variants in genes encoding gene products that regulate mitochondrial function. These genes are located either in the mitochondrial or in the nuclear genome. The TOMM7 gene encodes a regulatory subunit of the translocase of outer mitochondrial membrane (TOM) complex that plays an essential role in translocation of nuclear-encoded mitochondrial proteins into mitochondria. We report an individual with a homozygous variant in TOMM7 (c.73T>C, p.Trp25Arg) that presented with a syndromic short stature, skeletal abnormalities, muscle hypotonia, microvesicular liver steatosis, and developmental delay. Analysis of mouse models strongly suggested that the identified variant is hypomorphic because mice homozygous for this variant showed a milder phenotype than those with homozygous Tomm7 deletion. These Tomm7 mutant mice show pathological changes consistent with mitochondrial dysfunction, including growth defects, severe lipoatrophy, and lipid accumulation in the liver. These mice die prematurely following a rapidly progressive weight loss during the last week of their lives. Tomm7 deficiency causes a unique alteration in mitochondrial function; despite the bioenergetic deficiency, mutant cells show increased oxygen consumption with normal responses to electron transport chain (ETC) inhibitors, suggesting that Tomm7 deficiency leads to an uncoupling between oxidation and ATP synthesis without impairing the function of the tricarboxylic cycle metabolism or ETC. This study presents evidence that a hypomorphic variant in one of the genes encoding a subunit of the TOM complex causes mitochondrial disease.

Increased Serum-Immunoglobulin G4 Levels in a 12-Year-Old Male Patient With Central Diabetes Insipidus.

Immunoglobulin G4 (IgG4)-related disorders are characterized by tissue hypertrophy due to IgG4-positive cell infiltration and increased serum IgG4 levels. IgG4-related hypophysitis (IgG4-RH) is characterized by pituitary hypertrophy, IgG4-positive cell infiltration, central diabetes insipidus, and increased serum IgG4 levels. IgG4-RH is diagnosed through diagnostic criteria. A few cases of IgG4-RH in children have been reported. We report a case of CDI with increased serum IgG4 levels that failed to meet the diagnostic criteria of IgG4-RH. The patient developed polyuria and polydipsia at age 11 and was diagnosed as having idiopathic CDI at age 12. The patient was not treated with steroids and is well controlled with antidiuretic hormones. It has been reported that pediatric IgG4-RH differs from that of adults in several respects. We believe that the pediatric IgG4-RH may not fit the diagnostic criteria of adults. There may be also other cases of increased serum IgG4 levels in pediatric patients with idiopathic CDI. We do not know if they are subtypes of IgG4-RH or if serum IgG4 levels are by chance raised in CDI, however, we report them here because IgG4-RH in children may be different from that in adults.

Thyroid-related ophthalmopathy development in concurrence with growth hormone administration.

BACKGROUND: Thyroid stimulating hormone (TSH) receptor and local infiltrate lymphocytes have been considered as major pathological factors for developing thyroid-related ophthalmopathy. Overexpression of insulin-like growth factor-I (IGF-I) receptor has emerged as a promising therapeutic target for refractory patients. However, the relationship between activation of growth hormone (GH)/IGF-I receptor signaling and development or exacerbation of thyroid ophthalmopathy has not been elucidated. Herein we describe a case that provides further clarification into the association between thyroid-related ophthalmopathy and GH/IGF-I receptor signaling. CASE PRESENTATION: A 62-year-old Japanese female diagnosed with thyroid-related ophthalmopathy was admitted to Kurume University Hospital. She had received daily administration of GH subcutaneously for severe GH deficiency; however, serum IGF-I levels were greater than + 2 standard deviation based on her age and sex. She exhibited mild thyrotoxicosis and elevation in levels of TSH-stimulating antibody. Discontinuation of GH administration attenuated the clinical activity scores of her thyroid-related ophthalmopathy. Additionally, concomitant use of glucocorticoid and radiation therapies resulted in further improvement of thyroid-related ophthalmopathy. The glucocorticoid administration was reduced sequentially, followed by successful termination. Thereafter, the patient did not undergo recurrence of thyroid-related ophthalmopathy and maintained serum IGF-I levels within normal physiological levels. CONCLUSIONS: We describe here a case in which development of thyroid-related ophthalmopathy occurred upon initiation of GH administration. GH/IGF-I signaling was highlighted as a risk factor of developing thyroid-related ophthalmopathy. Additionally, aberrant TSH receptor expression was suggested to be a primary pathophysiological mechanism within the development of thyroid-related ophthalmopathy. Physicians should be aware of the risks incurred via GH administration, especially for patients of advanced age, for induction of thyroid-related ophthalmopathy.

Severe Hypernatremia in Combined Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State: A Case Report of Two Japanese Children.

As sodium level in diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) is usually low, normal, or slightly elevated, severe hypernatremia with DKA and/or HHS is rare. Case 1 was a 14-year-old boy, presenting with typical laboratory test values and symptoms consistent with DKA and HHS. His corrected sodium level, 172 mEq/L, might have occurred as a result of consuming 6 L/day of highly carbonated, carbohydrate- and sodium-rich drinks during the week preceding the diagnosis. This patient developed right lung artery thrombosis, which did not require treatment. Case 2 was a 10-year-old girl, presenting with typical laboratory test values and symptoms of DKA and HHS. Her corrected sodium level, 175 mEq/L, might have occurred as a result of large electrolyte-free water loss associated with osmotic diuresis. These two cases of patients presenting with DKA-HHS and severe hypernatremia are the first to be reported in Japan.

A case of combined 21-hydroxylase deficiency and CHARGE syndrome featuring micropenis and cryptorchidism.

BACKGROUND: 21-hydroxylase deficiency (21-OHD) is caused due to CYP21A2 gene variant. In males, the excess androgens produce varying degrees of penile enlargement and small testes. CHARGE syndrome (CS) has a broad spectrum of symptoms. In males, genital features such as micropenis and cryptorchidism are found in 48% of CS. There are no reports of patients with combined 21-OHD and CS; therefore, it is unknown whether the external genitalia shows penile enlargement or micropenis with/without cryptorchidism. CASE: A boy, born at 37 weeks and 5 days of gestational age with no consanguineous marriage, was admitted to our hospital due to congenital cleft lip, cleft palate, micropenis, cryptorchidism, and a ventricular septal defect. He had severe hyponatremia and hyperkalemia on day 10. He was diagnosed to have 21-OHD and CS. His external genitalia demonstrated both cryptorchidism and micropenis, but not penile enlargement. METHODS: DNA was extracted from peripheral leukocytes using standard procedures. Sanger sequence was performed in CYP21A2. Exome sequence was performed, and then, Sanger sequence was performed around variant in CHD7. RESULTS: Genetic screening for CYP21A2 gene was performed and compound heterozygous variants of c.293-13A/C>G (IVS2-13A/C>G) and c.518T>A (p.I172N) were detected in chromosome 6p21.3. His mother had been heterozygous variant of c.293-13A/C>G, and his father had been heterozygous variant of c.518T>A. Simultaneously, a de novo splicing acceptor alteration in c.7165-4 A>G, in chromodomain helicase DNA binding protein-7 (CHD7), located in chromosome 8q12 was detected, and the patient was diagnosed with 21-OHD and CS. CONCLUSION: Although these two disorders exhibit different modes of inheritance and their co-morbidity is extremely rare, we encountered one male patient who suffered from both 21-OHD and CS.

The first Japanese case of central precocious puberty with a novel MKRN3 mutation.

MKRN3, located on chromosome 15q11.2, encodes makorin ring-finger 3, which is an upstream suppressor of the hypothalamic-pituitary-gonadal axis. Mutation of this gene induces central precocious puberty (CPP). As MKRN3 is maternally imprinted, only the paternal allele is expressed. This is the first report of an 8-year-old Japanese girl with CPP caused by a novel frameshift mutation in MKRN3 (p.Glu229Argfs*3).

Developmental delay and failure to thrive in a 7-month-old baby boy with spontaneous transient Graves' thyrotoxicosis: a case report.

BACKGROUND: Thyroid dysfunction can induce developmental delay and failure to thrive in infancy. Congenital hypothyroidism is one of the common causes of these symptoms in infancy. By contrast, hyperthyroidism is a rare cause of these symptoms in infancy. CASE PRESENTATION: A 7-month-old Japanese baby boy was examined for developmental delay and failure to thrive. Blood tests were performed, which showed low levels of thyroid-stimulating hormone (<0.01 µU/mL) and high levels of free thyroxine (2.14 pg/mL). He was referred to our hospital at 8 months of age. His height was 64 cm (-2.7 standard deviation) and his weight was 6085 g (-2.5 standard deviation). No goiter was detected on examination. His thyrotropin receptor antibody was slightly high (3.9 IU/L), whereas thyroid stimulating antibody, anti-thyroglobulin antibody, and thyroid peroxidase antibody were within normal range. These blood findings indicated hyperthyroidism, most likely Graves' disease. His free thyroxine level decreased in the first month after our examination. No increased vascularity of his thyroid gland was noted. The technetium uptake of his thyroid gland in scintigraphy was relatively increased compared to the intake of his salivary gland. We elected to observe rather than treat with anti-thyroid medications. CONCLUSION: We have to rule out spontaneous transient Graves' thyrotoxicosis when babies have symptoms of developmental delay and fail to thrive.