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.
Aggrecan, encoded by ACAN, is a major proteoglycan component of the extracellular matrix in the growth plate and articular cartilage. Aggrecan provides the hydrated gel structure important for the load-bearing properties of joints and plays a key role in cartilage and bone morphogenesis. At least 25 pathological ACAN mutations have been identified in patients with highly variable phenotypes of syndromic or non-syndromic short stature. This review provides an overview of the current understanding of ACAN and the clinical and genetic findings concerning aggrecan-associated diseases.
Tohru Yorifuji, Reiko Horikawa, Tomonobu Hasegawa, Masanori Adachi, Shun Soneda, Masanori Minagawa, Shinobu Ida, Takeo Yonekura, Yoshiaki Kinoshita, Yutaka Kanamori, Hiroaki Kitagawa, Masato Shinkai, Hideyuki Sasaki, Masaki Nio, (on behalf of The Japanese Society for Pediatric Endocrinology and The Japanese
Society of Pediatric Surgeons)
Congenital hyperinsulinism is a rare condition, and following recent advances in diagnosis and treatment, it was considered necessary to formulate evidence-based clinical practice guidelines reflecting the most recent progress, to guide the practice of neonatologists, pediatric endocrinologists, general pediatricians, and pediatric surgeons. These guidelines cover a range of aspects, including general features of congenital hyperinsulinism, diagnostic criteria and tools for diagnosis, first- and second-line medical treatment, criteria for and details of surgical treatment, and future perspectives. These guidelines were generated as a collaborative effort between The Japanese Society for Pediatric Endocrinology and The Japanese Society of Pediatric Surgeons, and followed the official procedures of guideline generation to identify important clinical questions, perform a systematic literature review (April 2016), assess the evidence level of each paper, formulate the guidelines, and obtain public comments.
We recently published growth references for Japanese individuals with Noonan syndrome (NS). However, it is uncertain whether these references can be used to evaluate the longitudinal growth of children with NS. In addition, these charts did not include detailed values suitable for clinical practice, and they did not include weight-for-height (WFH) charts. In the present study, we validated the references and established new WFH charts for children with NS. In addition, we investigated the growth patterns of these children by comparing them with those of children with Turner syndrome (TS), as well as with those of the normal population. To validate our reference values, we enrolled 32 subjects from our previous study with data available at both a younger (≤ 5 yr) and an older age (≥ 15 yr). We then investigated longitudinal changes in NS-specific standard deviation scores (SDSs) for height in these subjects. There was no significant difference between the initial and later SDSs (mean difference: –0.12, 95% confidence interval: –0.26–0.023, P = 0.10), suggesting that the references could be applied in clinical practice. We also confirmed that the growth patterns of children with NS in each index are significantly different from those of children with TS. In conclusion, we confirmed auxological reference values for Japanese children with NS.
Neonatal diabetes mellitus (NDM) is an insulin-requiring monogenic form of diabetes that generally presents before six months of age. The following two types of NDM are known: transient NDM (TNDM) and permanent NDM (PNDM). Here we report on an infant with TNDM caused by a mutation (p.Gly832Cys) of the gene for the ATP binding cassette subfamily C member 8 (ABCC8). The patient exhibited hyperglycemia (600 mg/dL) at five weeks of age and insulin treatment was initiated. As genetic analysis identified a missense mutation within ABCC8, the insulin was replaced by glibenclamide at five months of age. Thereafter, the insulin was successfully withdrawn and his glycemic condition was well controlled at a dose of 0.0375 mg/kg/d. Since the patient’s blood glucose was under control and serum C-peptide levels were measurable, glibenclamide was stopped at 1 yr, 10 mo of age. The lack of DM relapsed to date confirms the TNDM diagnosis. In conclusion, when insulin is replaced with a sulfonylurea-class medication (SU) in NDM patients, serum C-peptide levels should be closely monitored and fine adjustment of SU dose is recommended.
Acute ingestion of thyroid hormone preparations is a common intoxication, with 181 cases in children <12 yr in 2009 in the Netherlands, but generally has a mild course. However, some reports show that even low dosages may cause serious events such as seizures, thyroid storm and coma. We report a 3 yr old boy case with an acute intoxication with high dose levothyroxine (0.5 mg/kg). We describe the proper management of levothyroxine intoxication in children. A 3-year-old boy with no notable medical history ingested sixty tablets of levothyroxine 150 µg. His vital-signs were normal and the only symptom during admission was a tachycardia the following day. Laboratory data showed elevated T3, fT3 and fT4 levels; and decrease TSH levels. He was treated prophylactically and therapeutically with activated charcoal and propranolol. Despite very high levels, his clinical symptoms were relatively mild. After clinical follow-up for 3 d he was discharged. We propose that children with thyroid hormone intoxication with either a levothyroxine dose >0.1 g/kg, a short interval since ingestion, symptomatic presentation, and/or a fT4 >100 pmol/l should be monitored in the hospital during at least 48–72 h post-ingestion and on an outpatient basis for 14 d.
Acrodysostosis is characterized by distinctive facial features and severe brachydactyly. Mutations in PRKAR1A or PDE4D are known to be responsible for this disease. Cases of hormonal resistance have been reported, particularly in patients with PRKAR1A mutations. The physical characteristics and endocrine function of pseudohypoparathyroidism type Ia is known to resemble acrodysostosis. We report the case of a 4-yr-old patient with a PRKAR1A mutation. He had characteristic facies with an upturned nose and cone-shaped epiphyses of most phalanges. These findings have not been reported as extensive for cases of pseudohypoparathyroidism type Ia. He also had TSH resistance from birth. We performed endocrinological stimulation tests to further evaluate his endocrine status. These examinations revealed resistance to TSH and PTH, but there was normal secretion of ACTH, GH, and cortisol. An Ellsworth-Howard test resulted in normal urinary cAMP excretion. This response differs from that of pseudohypoparathyroidism type Ia. In summary, the constellation of an upturned nose, cone-shaped epiphyses of most if not all phalanges, and PTH resistance with a normal urinary cAMP response may satisfactorily enable clinical diagnosis of acrodysostosis.
The first-line pharmacological treatment for patients with maturity-onset diabetes of the young type 1 (MODY1) and maturity-onset diabetes of the young type 3 (MODY3) are sulfonylureas (SUs) or insulin. However, several reports have suggested the possibility of using incretin-associated drugs, including dipeptidyl-peptidase-4 (DPP-4) inhibitors, for the treatment of patients with these types of MODY. Here we report a case of a pediatric patient with MODY1 who was successfully treated with a DPP-4 inhibitor, alogliptin. A 13-yr-old Japanese girl with diabetes was initially treated with insulin for 5 mo. After diagnosis of MODY1, confirmed via a genetic analysis, treatment was changed from insulin to alogliptin. SUs were prescribed temporarily, but monotherapy with alogliptin finally resulted in good glycemic control. After changing to alogliptin, the patient maintained optimal glycemic control with glycated hemoglobin levels of 6.3–7.0% while maintaining substantial β-cell function. No adverse events associated with alogliptin were observed. These results suggest that DPP-4 inhibitors may be a potential treatment for patients with MODY1 at the early stage of the disease when residual insulin secretion is still being sustained.
A 20-mo-old girl was brought to our department by her mother because of breast enlargement. She was diagnosed with premature thelarche. One month later, she returned to our hospital with a complaint of vaginal bleeding. During the subsequent 6 mo, her vaginal bleeding recurred every month while her breast development disappeared. We performed laboratory tests and imaging. At the end of 6 mo, we realized that her mother’s menstrual bleeding and the patient’s blood staining were concurrent. The mother confessed applying her vaginal flow to her daughter’s underwear. Factitious disorder should be included in the differential diagnosis of unexplained vaginal bleeding in childhood.
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