Summary
Objective
Loss‐of‐function mutations in IGSF1 result in X‐linked central congenital hypothyroidism (CeCH), occurring in isolation or associated with additional pituitary hormone deficits. ...Intrafamilial penetrance is highly variable and a minority of heterozygous females are also affected. We identified and characterized a novel IGSF1 mutation and investigated its associated phenotypes in a large Irish kindred.
Design, Patients and Measurements
A novel hemizygous IGSF1 mutation was identified by direct sequencing in two brothers with CeCH, and its functional consequences were characterized in vitro. Genotype‐phenotype correlations were investigated in the wider kindred.
Results
The mutant IGSF1 protein (c.2318T > C, p.L773P) exhibited decreased plasma membrane expression in vitro due to impaired trafficking from the endoplasmic reticulum. Ten hemizygous males and 11 heterozygous females exhibited characteristic endocrine deficits. Ireland operates a TSH‐based CH screening programme, which does not detect CeCH; therefore, genetic ascertainment preceded biochemical diagnosis of moderate CH in five of seven boys as well as their 75‐year‐old grandfather. Clinical features potentially attributable to hypothyroidism were variable; normal free T3 (FT3) and low/low normal reverse T3 (rT3) concentrations suggested that preferential deiodination of FT4 to FT3 may help maintain tissue euthyroidism in some individuals. However, neonatal jaundice, delayed speech or growth, and obesity were observed in seven subjects in whom diagnosis was delayed.
Conclusions
As observed with other IGSF1 mutations, p.L773P results in variably penetrant IGSF1 deficiency syndrome. Our observations emphasize the need for multi‐generation genetic ascertainment in affected families, especially where TSH‐based CH screening programmes may fail to detect CeCH at birth.
Full text
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
P41 Not your typical rickets case Beckett, Rachel; Heffernan, Emmeline
Abstracts,
06/2019, Volume:
104, Issue:
Suppl 3
Journal Article
Peer reviewed
Open access
PresentationA healthy caucasian 3 year old girl was referred due to bowing of her femora, apparent since she started walking at 13 months. She was reported to be clumsy and tire easily. There was no ...history of fractures or leg pain. Her height had dropped from the 75th centile to between the 25th and 50th centile. Initial investigations showed mildly low corrected calcium and phosphate, slightly raised alkaline phosphatase and a sufficient vitamin D level of 50nmol/L. She was treated with oral Vitamin D supplements. X-ray of knees was normal. On review after 6 months, bowing had progressed and height had fallen further. This led to the consideration of rarer forms of rickets.Further investigationsUrinary calcium creatinine ratio was normal at 0.07 but urinary phosphate: creatinine ratio was elevated at 4.36; with reduced tubular reabsorption of phosphate - in keeping with a diagnosis of×linked hypophosphataemic rickets. This was confirmed by detection of a mutation in the PHEX gene.Skeletal survey showed lower limb abnormalities, including flared metaphyses, widening of the growth plates and buttressing of the femur and tibia. Renal ultrasound showed no nephrocalcinosis. Parental blood tests showed a slightly low phosphate level in her mother.Progress and treatmentShe was treated with oral phosphate supplements and alfacalcidol. Since commencing treatment her growth has improved and she remains active but still tires easily. She was subsequently diagnosed with moderate sensorineural hearing loss, another feature of hypophosphataemic rickets, and has had bilateral hearing aids fitted.X linked hypophosphataemic ricketsRickets is a disorder of the growth plate, due to inadequate supply of phosphate to growing bones. Mutations in the PHEX gene cause increased levels of fibroblast growth factor 23 (FGF23), resulting in reduced absorption of phosphate in the proximal renal tubule. Although rare, it is the most common form of hereditary rickets, and usually presents in the first 2 years of life. Investigations show low serum phosphate and the key feature is significant phosphaturia (calculated by TmP/GFR). Patients are at increased risk of dental complications, enthesopathy, lumbar lordosis and hearing impairment. Phosphate supplements replace renal losses and calcitriol increases phosphate absorption from the gut and reduces PTH, preventing nephrocalcinosis. A new treatment, Burosumab is a monoclonal IgG1 antibody that binds excess FGF23. This normalises phosphate levels and improves bone mineralisation.
Infant with macroglossia Mullan, Kathryn; Keel, Cheryl; McKenna, Martha ...
Archives of disease in childhood. Education and practice edition,
06/2024, Volume:
109, Issue:
3
Journal Article
mutations cause neonatal diabetes mellitus that can be transient (TNDM) or, less commonly, permanent (PNDM); ∼90% of individuals can be treated with oral sulfonylureas instead of insulin. Previous ...studies suggested that people with
PNDM require lower sulfonylurea doses and have milder neurological features than those with
PNDM. However, these studies were short-term and included combinations of
-PNDM and
-TNDM. We aimed to assess the long-term glycemic and neurological outcomes in sulfonylurea-treated
-PNDM.
We studied all 24 individuals with
PNDM diagnosed in the U.K., Italy, France, and U.S. known to transfer from insulin to sulfonylureas before May 2010. Data on glycemic control, sulfonylurea dose, adverse effects including hypoglycemia, and neurological features were analyzed using nonparametric statistical methods.
Long-term data were obtained for 21 of 24 individuals (median follow-up 10.0 range 4.1-13.2 years). Eighteen of 21 remained on sulfonylureas without insulin at the most recent follow-up. Glycemic control improved on sulfonylureas (presulfonylurea vs. 1-year posttransfer HbA
7.2% vs. 5.7%,
= 0.0004) and remained excellent long-term (1-year vs. 10-year HbA
5.7% vs. 6.5%,
= 0.04),
= 16. Relatively high doses were used (1-year vs. 10-year dose 0.37 vs. 0.25 mg/kg/day glyburide,
= 0.50) without any severe hypoglycemia. Neurological features were reported in 13 of 21 individuals; these improved following sulfonylurea transfer in 7 of 13. The most common features were learning difficulties (52%), developmental delay (48%), and attention deficit hyperactivity disorder (38%).
Sulfonylurea treatment of
-PNDM results in excellent long-term glycemic control. Overt neurological features frequently occur and may improve with sulfonylureas, supporting early, rapid genetic testing to guide appropriate treatment and neurodevelopmental assessment.
Summary
Objective
Loss‐of‐function mutations in
IGSF
1
result in X‐linked central congenital hypothyroidism (Ce
CH
), occurring in isolation or associated with additional pituitary hormone deficits. ...Intrafamilial penetrance is highly variable and a minority of heterozygous females are also affected. We identified and characterized a novel
IGSF
1
mutation and investigated its associated phenotypes in a large Irish kindred.
Design, Patients and Measurements
A novel hemizygous
IGSF
1
mutation was identified by direct sequencing in two brothers with Ce
CH
, and its functional consequences were characterized in vitro. Genotype‐phenotype correlations were investigated in the wider kindred.
Results
The mutant
IGSF
1 protein (c.2318T > C, p.L773P) exhibited decreased plasma membrane expression in vitro due to impaired trafficking from the endoplasmic reticulum. Ten hemizygous males and 11 heterozygous females exhibited characteristic endocrine deficits. Ireland operates a
TSH
‐based
CH
screening programme, which does not detect Ce
CH
; therefore, genetic ascertainment preceded biochemical diagnosis of moderate
CH
in five of seven boys as well as their 75‐year‐old grandfather. Clinical features potentially attributable to hypothyroidism were variable; normal free T3 (
FT
3) and low/low normal reverse T3 (
rT
3) concentrations suggested that preferential deiodination of
FT
4 to
FT
3 may help maintain tissue euthyroidism in some individuals. However, neonatal jaundice, delayed speech or growth, and obesity were observed in seven subjects in whom diagnosis was delayed.
Conclusions
As observed with other
IGSF
1 mutations, p.L773P results in variably penetrant
IGSF
1 deficiency syndrome. Our observations emphasize the need for multi‐generation genetic ascertainment in affected families, especially where
TSH
‐based
CH
screening programmes may fail to detect Ce
CH
at birth.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Context:
Released by the US Department of Health and Human Services (HHS) every decade since 1980, Healthy People identifies science-based objectives with targets to monitor progress and motivate and ...focus action. Healthy People 2030 is the current iteration of the Healthy People initiative.
Program:
Healthy People 2030 includes 3 sets of measures—Healthy People 2030 objectives, Leading Health Indicators (LHIs), and Overall Health and Well-being Measures (OHMs). Collectively, these components of Healthy People 2030 drive progress toward the initiative's vision of “a society in which all people can achieve their full potential for health and well-being across the life span.”
Implementation:
The Healthy People 2030 LHIs and OHMs were developed with input from multiple subject matter experts and launched in December 2020. Designed as an entry point for users interested in improving the health of their communities and selected for their ability to improve health and well-being, the LHIs will be assessed annually. As broad, global outcome measures of overall health and well-being, the OHMs will be assessed at least 3 times before 2030.
Evaluation:
The 23 LHIs are a subset of Healthy People 2030 core objectives that have been selected to drive action toward improved health and well-being. LHIs are intended to help organizations, communities, and states across the nation focus resources and efforts to improve the health and well-being of all people. The OHMs include 8 broad, global outcome measures of overall health and well-being that help assess progress toward the Healthy People 2030 vision. The Healthy People 2030 OHMs include the addition of a measure of overall well-being.
Discussion:
Together with the Healthy People 2030 objectives, the LHIs and OHMs provide a plan of action to improve the health and well-being of the nation through a framework for assessing progress, addressing health disparities and social determinants of health, and advancing health equity.
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