Abstract
Temple syndrome is a rare imprinting disorder, caused by alterations in the critical imprinted region 14q32 of chromosome 14. It is characterized by pre- and postnatal growth retardation, truncal hypotonia and facial dysmorphism in the neonatal period. We report an 18-year-old girl with a late diagnosis of Temple syndrome presenting with all typical signs and symptoms including small for gestational age at birth, feeding difficulties, muscle hypotonia and delayed developmental milestones, central precocious puberty, truncal obesity and reduced growth. The patient is the second reported in the literature with signs of clinical and biochemical hyperandrogenism and the first treated with Dehydrocortisone®, with a good response. The clinical diagnosis of this patient was made after long-term follow up at a single center for rare endocrine diseases, and a molecular genetics diagnosis of complete hypomethylation of 14q32 chromosome imprinting center (DLK/GTL2) was recently established. Growth hormone treatment was not given and although precocious puberty was treated in line with standard protocols, her final height remained below the target range. Increased awareness of Temple syndrome and timely molecular diagnosis enables improvement of clinical care of these patients as well as prevention of inherent metabolic consequences.
What is already known on this topic?
The presented patient’s history and disease course over more than 18 years are consistent with other reported Temple syndrome patients in the literature, regardless of the late diagnosis and childhood follow-up as a suspected other conditions.
What this study adds?
The description of the case shows the significance of multidisciplinary life-long follow-up for the patients with rare endocrine disease. Our patient is the only one genetically confirmed in Bulgaria and the second in the world with signs of clinical and biochemical hyperandrogenism. This is an intriguing finding that deserves future studies. The article is significant because it follows the trend for developing and expansion of the Rare Endocrine Networks all over the world in order to provide specialized multidisciplinary care for the rare patients.
Introduction
We present a case report and long-term follow-up of a patient with a late diagnosis of Temple syndrome, to raise awareness among clinicians of the importance of timely diagnosis of this disease. Although some of the patient’s conditions arose during her childhood, and she was treated in line with standard protocols, her final outcomes are poorer than she might have achieved if her diagnosis had been established at an earlier age. The report also highlights novel endocrine findings.
Temple syndrome was first described by Temple et al. (1) in 1991, who reported a male, aged 18 years, who inherited a balanced Robertsonian translocation from his mother and as a result had maternal uniparental disomy of chromosome 14 (mUPD14). Gillessen-Kaesbach et al. (2) published eight patients with clinical features of mUPD14 in 2008, expanding the phenotype.
Imprinting defects in Temple syndrome lead to incorrect expression of imprinted genes on chromosome 14q32. Maternally expressed genes in 14q32, MEG3, RTL1as and MEG8, as well as the paternally expressed genes, DLK1 and RTL1, are regulated by two differentially methylated regions (DMR), both methylated on the paternal and unmethylated on the maternal copy (3). Temple et al. (4) reported a patient with aberrant loss of paternal methylation at the 14q32 IG-DMR. A year later, Buiting et al. (5) described three patients with similar genetic characteristics who showed loss of methylation of the paternal copy of the DLK1-GTL2-DIO3 domain. It is now established that mUPD14, loss of methylation and rare paternal deletions of the locus can cause Temple syndrome (6, 7).
Intrauterine growth retardation, low birth weight, early neonatal muscular hypotonia, delayed early motor milestones and feeding problems are the clinical hallmarks of Temple syndrome (ORPHA:254516, OMIM#616222) (1, 2). Postnatal clinical course is further characterised by persisting growth retardation, subtle facial dysmorphism (broad forehead and short nose with a wide nasal tip), joint hypermobility, small hands and feet, precocious puberty, truncal obesity and short stature at adulthood (1, 8, 9, 10). Speech delay can be present in infancy to early childhood, but verbal capacity usually normalizes in childhood. Some patients have intellectual delay, and autism has been reported (11, 12, 13). Patients are prone to late metabolic complications, particularly obesity (8, 10).
Informed consent for this publication was obtained from the patient and the family.
Case Report
We report an 18-year-old girl with Temple syndrome. Our patient is the first child of non-consanguineous parents, with a family history of short stature (the paternal grandmother) without other clinical associations.
The singleton pregnancy was uneventful. Delivery was natural at 38th gestational week, with meconium-stained amniotic fluid. Resuscitation was required initially. The girl was small for gestational age (SGA) with a birth weight at the 2nd percentile (2350 g), birth length at the 25th percentile (48 cm) and head circumference at the 10th percentile (34 cm), (https://www.cdc.gov/growthcharts/clinical_charts.htm). Truncal hypotonia, poor growth and lack of weight gain were noticed in the neonatal and early infant period. Nasogastric tube feeding was introduced because of feeding difficulties until three months of age.
At the age of 7 months, Silver-Russell syndrome (SRS) was suspected (Table 1), but genetic testing for maternal UPD 7 and methylation at H19 gave negative results.
The girl demonstrated motor and speech delay. Her first steps were at 18 months and first words at the age of two years, with the help of a speech therapist. At the age of 14 months she had an episode of severe hypoglycaemia with generalized seizure. The inability to endure long periods of fasting remained until pre-school age. The family was educated to recognize, measure and cope with hypoglycaemia at home.
Between birth and six years of age, the patient’s height was below the 3rd percentile on the Centers for Disease Control and Prevention appropriate for age and sex growth chart. After four years of age she started to gain weight and moved from the 25th to the 75th weight percentile with no improvement in linear growth (Figure 1). At the age of 6 years and 10 months, because of a further decrease of growth velocity, recombinant human growth hormone (rhGH) treatment was prescribed under the approved indication of being born SGA without postnatal catch-up. During the process of supplying the family with rhGH, the patient presented with signs of precocious puberty. Over three months, at the age of 7 years 2 months, she developed thelarche, pubic hair, and increased growth velocity. Her bone age accelerated to 9.5 years by the Greulich and Pyle method. Due to the rapidity of pubertal progression luteinizing hormone releasing hormone (LHRH) agonist treatment (triptorelin 3.75 mg i.m. every 28 days) was started at the age of 7 years 5 months, with good compliance. Of note, rhGH was never used.
The girl was treated until 11 years of age without further pubertal progression and with decreased growth velocity, but with continuing rapid weight gain. The discrepancy between her short stature and progressive truncal obesity increased with time (Figure 1). Prader-Willi syndrome (PWS) was suspected at 10 years of age because of the clinical overlap in the neonatal period, some of the dysmorphic features and most of all, the uncontrollable weight gain (Figure 2). However, the methylation test gave a negative result for PWS. Facial acne appeared for the first time at the age of nine years.
After LHRH agonist therapy was withdrawn, rapid pubertal progression followed, with menarche at 12 years 4 months. Elevated 17-hydroxyprogesterone (17-OHP), testosterone, and androstendione were detected at the age of 16 years 10 months in parallel with worsening of acne, complaints of oily hair and mild hirsutism (Ferriman-Gallwey score of 13 out of 36 points). Prednisone was started at a daily dose of 5 mg prior to night sleep for six months. An attempt was made to reduce prednisone to 2.5 mg/d thereafter but because of a worsening of hyperandrogenism the dose was again increased to 5.0 mg/d (Table 2).
The accumulating features and events during the whole 18-year patient follow-up led to a clinical diagnosis of Temple syndrome, which was molecularly confirmed at the Wessex Regional Genetic Laboratory, United Kingdom, after written informed consent from the patient and the family. The patient’s DNA showed complete hypomethylation of the DLK1/GLT2 imprinting centre on chromosome 14q32, consistent with the diagnosis of Temple syndrome.
After diet and physical activity counseling throughout childhood and adolescence, the patient lost weight and is now controlling her weight successfully. Her adult height is 141 cm [-4.76 standard deviation score (SDS)], 5 cm below the lower limit of the target range, with current BMI of 23.6 kg/m2 (0.48 SDS) (Figure 1). The patient’s metabolic markers (blood glucose level, insulin level, homeostasis model assessment-estimated-insulin resistance, lipids) are all within reference range. Facial acne improved with time and treatment. Clinical and biochemical hyperandrogenism abated and gradual improvement in menstrual regularity followed. She is seen every six months because of the increased risk of metabolic complications. Transition to adult endocrinologists at the same rare endocrine diseases expert center is ongoing.
Discussion
The presented girl is the first described and confirmed Bulgarian patient with Temple syndrome. Her history demonstrates the natural history of this condition after careful follow-up over 18 years in a single center, and provides insights into the complex growth pattern that is observed in the absence of rhGH treatment. To our knowledge, there are only two other reports of patients with late diagnosis of Temple syndrome, detailing long term follow up of 13 years and at 33 years (6, 13). Previous testing for two imprinting conditions (SRS and PWS) adds to the literature showing the clinical similarity between these conditions and patients with Temple syndrome, and showing that multi-locus imprinting investigation is warranted if an imprinting disorder is suspected (14).
Clinical features of Temple syndrome are heterogeneous and age dependent (15, 16). Patients often present with some of the features of SRS (17). Kagami et al. (10) showed that SRS-like phenotype was present in 20% of patients with Temple syndrome, differential diagnosis being particularly difficult in infancy (11, 18). Genetic confirmation of Temple syndrome has been reported among patients previously tested for PWS (15, 19).
Evidence clearly indicates that Temple syndrome is more prevalent than previously recognized (8, 10, 16). When clinical findings for SRS and PWS are observed and there is no genetic confirmation, Temple syndrome should be the next suspected condition.
The final diagnosis, established at the age of 18 years in the presented patient, is an important achievement for her. Although there is currently no causal treatment for Temple syndrome, concomitant features and especially metabolic complications can be prevented or treated (13). A failure of early diagnosis prevented the patient from accessing rhGH treatment under the SGA indication for children without postnatal catch-up. However, not all patients with Temple syndrome are eligible for rhGH under this indication, because their early growth parameters may fall within low normal ranges (20). Children who were treated with a median rhGH dose of 0.040 mg/kg/day, had a median 1.31 SDS increase in height for the first year and increased height velocity of 5.30 cm/year. They had similar short-term response to rhGH as other treated SGA patients (21). An established diagnosis of Temple syndrome could facilitate the treatment process, and would have led to rhGH treatment of the current patient regardless of the difficulties in the supplies at that time. The missed opportunity for therapy with rhGH is one of the shortcomings in the patient’s management.
As mentioned above, at the age of 16 years the patient presented with signs of hyperandrogenism. To the best of our knowledge, there is only one published report of a patient with Temple syndrome with isolated hypomethylation of the 14q32 imprinted DLK1/MEG3 region who had clinical signs of hyperandrogenism (6). Our patient’s results indicated markedly elevated basal 17-OHP. Although ACTH stimulation test was not done, the findings were consistent with non-classical congenital adrenal hyperplasia (NCAH). According to Nördenstrom and Falhammar, basal 17-OHP of above 15 nmol/L (4.7 ng/mL) and/or ACTH-stimulated 17-OHP of more than 30 nmol/L (9.43 ng/mL), in females during the follicular phase of the menstrual cycle, is considered to be diagnostic for NCAH (22). For that reason, the clinical diagnosis of NCAH was established in our patient and therapy with prednisone was prescribed, with good response nine months after the start of treatment (Table 2). Further genetic testing may be warranted to exclude NCAH. Hyperandrogenism may also be a metabolic consequence of Temple syndrome that is not yet investigated in patients of the appropriate age.
Patients with Temple syndrome may develop obesity, type 2 diabetes mellitus, hypercholesterolemia/hyperlipidemia, and obstructive sleep apnea (12, 13). To date, the patient has not shown any of these features, most likely because of her current successful weight control.
Conclusion
The clinical history of this patient over more than 18 years of follow up is consistent with other reports of patients with Temple syndrome who received late diagnosis after earlier clinical investigation for SRS and PWS. The observation of adrenal hyperandrogenism is an intriguing finding that deserves future study and further investigation. Outcomes in Temple syndrome may be improved by aggregation of knowledge, development of targeted, multidisciplinary, life-long care, and education of health professionals to enable patients with Temple syndrome to access earlier diagnosis and therefore better clinical management.
