In this case report, we present a novel mutation in Lim-homeodomain (LIM-HD) transcription factor, LHX3, manifesting as combined pituitary hormone deficiency (CPHD). This female patient was originally diagnosed in Egypt during infancy with Diamond Blackfan Anemia (DBA) requiring several blood transfusions. Around 10 months of age, she was diagnosed and treated for central hypothyroidism. It was not until she came to the United States around two-and-a-half years of age that she was diagnosed and treated for growth hormone deficiency. Her response to growth hormone replacement on linear growth and muscle tone were impressive. She still suffers from severe global development delay likely due to delay in treatment of congenital central hypothyroidism followed by poor access to reliable thyroid medications. Her diagnosis of DBA was not confirmed after genetic testing in the United States and her hemoglobin normalized with hormone replacement therapies. We will review the patient’s clinical course as well as a review of LHX3 mutations and the associated phenotype.
Describe an unusual presentation of undertreated pituitary hormone deficiencies in early life
Combined pituitary hormone deficiency due to a novel mutation in pituitary transcription factor, LHX3
Describe the clinical phenotype of combined pituitary hormone deficiency due to LHX3 mutations
George StoyleDepartment of Paediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester, UK Manchester Medical School, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
Siddharth BankaManchester Centre for Genomic Medicine, Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University, NHS Foundation Trust, Health Innovation Manchester, Manchester, UK
Elizabeth A JonesManchester Centre for Genomic Medicine, Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University, NHS Foundation Trust, Health Innovation Manchester, Manchester, UK
Wiedemann–Steiner Syndrome (WSS) is a rare condition characterised by short stature, hypertrichosis of the elbow, intellectual disability and characteristic facial dysmorphism due to heterozygous loss of function mutations in KMT2A, a gene encoding a histone 3 lysine 4 methyltransferase. Children with WSS are often short and until recently, it had been assumed that short stature is an intrinsic part of the syndrome. GHD has recently been reported as part of the phenotypic spectrum of WSS. We describe the case of an 8-year-old boy with a novel heterozygous variant in KMT2A and features consistent with a diagnosis of WSS who also had growth hormone deficiency (GHD). GHD was diagnosed on dynamic function testing for growth hormone (GH) secretion, low insulin-like growth factor I (IGF-I) levels and pituitary-specific MRI demonstrating anterior pituitary hypoplasia and an ectopic posterior pituitary. Treatment with GH improved height performance with growth trajectory being normalised to the parental height range. Our case highlights the need for GH testing in children with WSS and short stature as treatment with GH improves growth trajectory.
Growth hormone deficiency might be part of the phenotypic spectrum of Wiedemann–Steiner Syndrome (WSS).
Investigation of pituitary function should be undertaken in children with WSS and short stature. A pituitary MR scan should be considered if there is biochemical evidence of growth hormone deficiency (GHD).
Recombinant human growth hormone treatment should be considered for treatment of GHD.
Deletion of chromosome 2q37 results in a rare congenital syndrome known as brachydactyly mental retardation (BDMR) syndrome; a syndrome which has phenotypes similar to Albright hereditary osteodystrophy (AHO) syndrome. In this report, we describe a patient with AHO due to microdeletion in long arm of chromosome 2 [del(2)(q37.3)] who had growth hormone (GH) deficiency, which is a unique feature among reported BDMR cases. This case was presented with shortening of the fourth and fifth metacarpals which along with AHO phenotype, brings pseudopseudohypoparathyroidism (PPHP) and pseudohypoparathyroidism type Ia (PHP-Ia) to mind; however, a genetic study revealed del(2)(q37.3). We recommend clinicians to take BDMR in consideration when they are faced with the features of AHO; although this syndrome is a rare disease, it should be ruled out while diagnosing PPHP or PHP-Ia. Moreover, we recommend evaluation of IGF 1 level and GH stimulation test in patients with BDMR whose height is below the 3rd percentile.
Clinicians must have brachydactyly mental retardation (BDMR) syndrome in consideration when they are faced with the features of Albright hereditary osteodystrophy.
Although BDMR syndrome is a rare disease, it should be ruled out while diagnosing PPHP or PHP-Ia.
Evaluation of IGF1 level in patients diagnosed with BDMR whose height is below the 3rd percentile is important.
Isolated Growth Hormone Deficiency (IGHD) is a rare cause of short stature, treated with the standard regimen of subcutaneous synthetic growth hormone (GH). Patients typically achieve a maximum height velocity in the first year of treatment, which then tapers shortly after treatment is stopped. We report a case of a 9-year-old male who presented with short stature (<3rd percentile for age and race). Basal hormone levels showed undetectable serum IGF1. Skeletal wrist age was consistent with chronologic age. Cranial MRI revealed no masses or lesions. Provocative arginine-GH stimulation testing demonstrated a peak GH level of 1.4 ng/mL. Confirmatory genetic testing revealed a rare autosomal recessive single-nucleotide polymorphism (SNP) with mutational frequency of 2%. GH supplementation was started and pursued for 2 years, producing dramatically increased height velocity. This velocity persisted linearly through adolescence, several years after treatment had been discontinued. Final adult height was >95th percentile for age and race. In conclusion, this is a case of primary hypopituitarism with differential diagnosis of IGHD vs Idiopathic Short Stature vs Constitutional Growth Delay. This case supports two objectives: Firstly, it highlights the importance of confirmatory genetic testing in patients with suspected, though diagnostically uncertain, IGHD. Secondly, it demonstrates a novel secondary growth pattern with implications for better understanding the tremendous variability of GH treatment response.
GHD is a common cause of growth retardation, and IGHD is a specific subtype of GHD in which patients present solely with short stature.
The standard treatment for IGHD is subcutaneous synthetic GH until mid-parental height is reached, with peak height velocity attained in the 1st year of treatment in the vast majority of patients.
Genetic testing should be strongly considered in cases of diagnostic uncertainty prior to initiating treatment.
Future investigations of GH treatment response that stratify by gene and specific mutation will help guide treatment decisions.
Response to treatment in patients with IGHD is variable, with some patients demonstrating little to no response, while others are ‘super-responders.’
Estrogen is used to induce puberty in peripubertal girls with hypogonadism. Although both synthetic and natural forms are available, along with different routes of administration, in the UK oral ethinyl estradiol and the low-dose oral contraceptive pill are commonly used as hormone replacement therapy for practical reasons. We present five peripubertal girls (aged 12.5–14.9 years) with hypogonadism (two with primary hypogonadism due to Turner syndrome and three with central (secondary) hypogonadism as part of multiple pituitary hormone deficiency) who for a variety of reasons have received milligram doses of estradiol (E2) in error for between 6 weeks and 6 months, instead of the expected microgram doses of ethinyl estradiol. Although there are no direct comparisons in peripubertal girls between synthetic and natural estrogens, all girls had vaginal bleeding whilst receiving the milligram doses and have ended up with reduced final heights, below the 9th centile in 1 and below the 2nd centile in 4. Whilst reduction in final height may be part of the underlying condition (especially in Turner syndrome) the two girls with height predictions performed prior to receiving the estrogen overdose have not achieved their predicted height. Estrogen is one of the few drugs which is available in both milligram and microgram formulations. Clinicians need to be alert to the possibility of patients receiving the wrong formulation and dosage in error.
Girls with primary and secondary gonadal failure require assistance with pubertal induction.
Although several different formulations and route of administration are available, for practical reasons, the majority of girls in the UK receive oral ethinyl estradiol.
Estrogen preparations are available in both milligram and microgram formulations, with potential for receiving the wrong dose.
Girls receiving milligram rather than microgram preparations all had vaginal bleeding and a short final height.
Isolated GH deficiency type IA (IGHDIA) is an infrequent cause of severe congenital GHD, often managed by pediatric endocrinologists, and hence few cases in adulthood have been reported. Herein, we describe the clinical status of a 56-year-old male with IGHDIA due to a 6.7 kb deletion in GH1 gene that encodes GH, located on chromosome 17. We also describe phenotypic and biochemical parameters, as well as characterization of anti-GH antibodies after a new attempt made to treat with GH. The height of the adult patient was 123 cm. He presented with type 2 diabetes mellitus, dyslipidemia, osteoporosis, and low physical and psychological performance, compatible with GHD symptomatology. Anti-GH antibodies in high titers and with binding activity (>101 IU/ml) were found 50 years after exposure to exogenous GH, and their levels increased significantly (>200 U/ml) after a 3-month course of 0.2 mg/day recombinant human GH (rhGH) treatment. Higher doses of rhGH (1 mg daily) did not overcome the blockade, and no change in undetectable IGF1 levels was observed (<25 ng/ml). IGHDIA patients need lifelong medical surveillance, focusing mainly on metabolic disturbances, bone status, cardiovascular disease, and psychological support. Multifactorial conventional therapy focusing on each issue is recommended, as anti-GH antibodies may inactivate specific treatment with exogenous GH. After consideration of potential adverse effects, rhIGF1 treatment, even theoretically indicated, has not been considered in our patient yet.
Severe isolated GHD may be caused by mutations in GH1 gene, mainly a 6.7 kb deletion.
Appearance of neutralizing anti-GH antibodies upon recombinant GH treatment is a characteristic feature of IGHDIA.
Recombinant human IGF1 treatment has been tested in children with IGHDIA with variable results in height and secondary adverse effects, but any occurrence in adult patients has not been reported yet.
Metabolic disturbances (diabetes and hyperlipidemia) and osteoporosis should be monitored and properly treated to minimize cardiovascular disease and fracture risk.
Cerebral magnetic resonance imaging should be repeated in adulthood to detect morphological abnormalities that may have developed with time, as well as pituitary hormones periodically assessed.