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Table of Contents
CASE REPORT
Year : 2022  |  Volume : 5  |  Issue : 3  |  Page : 309-312

Atypical presentation of pallister–Hall syndrome with central precious puberty


1 Pediatric Division, Department of Clinical Science, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
2 Medical Genetics Division, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
3 Pediatric Endocrinology Division, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia

Date of Submission18-Dec-2021
Date of Acceptance17-May-2022
Date of Web Publication08-Jul-2022

Correspondence Address:
Amal Ali Alhakami
Department of Clinical Science, Division Pediatric, College of Medicine, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jnsm.jnsm_157_21

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  Abstract 


Pallister–Hall syndrome (PHS) is a rare, autosomal dominant genetic disorder. The phenotypic features of the syndrome include hypothalamic hamartoma, polydactyly, craniofacial anomalies, and other malformations. This case report describes a 5-year-old girl with Central precocious puberty (CPP) due to the presence of suprasellar hypothalamic hamartoma. With a history of polydactyl, suspicion of PHS was made, and the genetic test showed a novel GLI3 gene mutation. CPP is treated with gonadotropin-releasing hormone agonist. In addition to CPP, an extensive endocrine evaluation revealed central hypothyroidism while other pituitary functions were intact. The variable clinical phenotype of PHS makes it challenging to diagnose early, especially in the sporadic form. However, suspicion of these cases and early diagnosis leads to a better outcome as many endocrine features may evolve during follow-up, which necessitates interventions.

Keywords: Central precocious puberty, hypothalamic hamartomas, Pallister–Hall syndrome, postaxial polydactyly


How to cite this article:
Omer HG, Alhakami AA, Alghamdi MA, Al Khalifah RA. Atypical presentation of pallister–Hall syndrome with central precious puberty. J Nat Sci Med 2022;5:309-12

How to cite this URL:
Omer HG, Alhakami AA, Alghamdi MA, Al Khalifah RA. Atypical presentation of pallister–Hall syndrome with central precious puberty. J Nat Sci Med [serial online] 2022 [cited 2022 Aug 17];5:309-12. Available from: https://www.jnsmonline.org/text.asp?2022/5/3/309/350297




  Introduction Top


Pallister–Hall syndrome (PHS) is a rare genetic disorder named after Judith Hall and Philip Pallister, who were the first to describe the condition in six infants in 1980. It was described as a neonatally lethal malformation syndrome of hypothalamic hematoma (HH), postaxial polydactyly, and imperforate anus. In addition, other abnormalities such as neuropathological and visceral abnormalities were reported later.[1],[2] This complex syndrome is caused by a pathogenic mutation in the GLI3 gene.[3],[4]

Central precocious puberty (CPP) is the main endocrine manifestation in PHS that is secondary to HH.[5] Herein, we discuss the unusual presentation of PHS in a 3-month-old infant in the context of a novel GLI3 gene mutation and describe the clinical evolution before and after the surgical laser ablation.


  Case Report Top


This is a 5-year-old girl diagnosed with precocious puberty at the age of 11 months. She is the first child of consanguineous marriage. She was born vaginally after an uneventful pregnancy. Upon birth, she was noted to have bilateral hand and left foot postaxial polydactyly that was considered an isolated condition and surgically removed at the age of 3 months. At the age of 6 months, she developed vaginal bleeding for 3 days, this happened again at the age of 9 months and 11 months. She also had bilateral development of breast tissue that started at age of 3 months; however, parents were told that those manifestations were likely normal and related to maternal hormones during pregnancy. Her growth was noticed to be normal by her parents, she did not have other secondary sexual characteristics, and her system review was unremarkable.

At the time of presentation, clinical examination revealed no dysmorphic features, midline defect, and normal epiglottis. She had a normal ophthalmological examination. Her growth parameters on the WHO growth charts length 76 cm (75th percentile), weight 12.6 kg (>98th percentile), and weight/length >98th percentile. Her developmental milestones were appropriate for her age. She had breast Tanner Stage III, no axillary or pubic hair, estrogenized vaginal mucosa with no clitoromegaly.

Laboratory workup revealed normal thyroid-stimulating hormone (TSH) 4.8 mIU/L (normal 0.2–5) and free thyroxin (FT4) 17.6 pmol/L (normal 12–22). The luteinizing hormone (LH)-releasing hormone stimulation test showed pubertal LH response with high estrogens [Table 1]. The serum alpha-fetoprotein level was 7.5 ng/ml, and beta-human chorionic gonadotropin qualitative was 0.100 mIu/L; both were normal for age. Prolactin level was 378 ng/ml (normal 3–24). The adrenocorticotropic hormone (ACTH) stimulation test revealed ACTH at baseline 10.7 Pmol/L (normal 2.2–13), and baseline serum cortisol was 170.5 nmol/l with a peak of 879.7 nmol/l at 60 min poststimulation indicating intact adrenocortical access. Liver enzymes and renal profile were normal. Bone age according to the Greulich and Pyle atlas was corresponding to 3 years at the chronological age of 11 months [Figure 1]. Ultrasound evaluation for the pelvis showed uterus 5 cm × 1.6 cm × 1.3 cm in diameters with no remarkable focal abnormalities, right ovary measures 1 cm × 1 cm, and left ovary 1 cm × 1.2 cm. Magnetic resonance imaging (MRI) of the brain showed large type 4 Delalande suprasellar hypothalamic hamartoma measuring 3 cm × 2.8 × 2.3 cm with extension above and below the floor of the third ventricle and optic chiasm with optic nerves stretched. The mass extends posteriorly into the interpeduncular cistern and splays the cerebral peduncles laterally [Figure 2].
Figure 1: Small bony remnant from the extracted postaxial polydactyl (Pallister hall syndrome is associated with polydactyly)

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Figure 2: large suprasellar mass measuring 3 cm × 2.8 cm × 2.3 cm (suprasellar hypothalamic hamartoma causing CPP)

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Table 1: Luteinizing hormone-releasing hormone stimulation test

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Treatment with Leuprolide 3.75 mg intramuscularly injection monthly was started based on the diagnosis of CPP secondary to the presence of HH. Pubertal signs and hormonal levels were well suppressed to prepubertal levels. However, at the age of 13 months, the parents noticed episodes of laughing and crying that were confirmed to be gelastic seizures. Electroencephalography showed high voltage spikes over the right posterior quadrant with maximum absolute voltage over the right occipital area; no seizure was recorded. Therefore, she was started on carbamazepine. A month later, the parents noticed a dramatic weight increase of 4 kg. Repeated TSH was 1.63 mIU/L and FT4 was 10.9 pmol/L indicating secondary hypothyroidism. Therefore, she was started on levothyroxine 25 μg orally once daily.

PHS was considered based on the presence of postaxial polydactyly and HH, and molecular testing was sent for GLI3 mutation. However, her parents did not have any suggestive features for PHS. The genetic testing revealed a novel heterozygous likely pathogenic variant, NM_000168.5: c. 2396 dup p (lys 800*), in the GLI3 gene, which creates a premature stop codon. The variant has been confirmed by Sanger sequencing, it is classified as likely pathogenic (Class 2) according to the recommendations of the American College of Medical Genetics and Genomics. The known familial likely pathogenic variant has not been identified by targeted GLI3 gene sequencing in both parents which confirms that the variant detected in the affected child occurred de novo. The de novo occurrence of the variant and the clinical consistency of the phenotype and the genotype suggest further the pathogenicity of the variant and confirm the genetic diagnosis of an autosomal dominant GLI3-related disorder.

Due to the concerns regarding the future impact of the tumor on optic nerves and partially controlled gelastic seizures, the parents saw a second opinion for surgical intervention. She underwent stereotactic laser ablation of the hypothalamic hamartoma at the age of 2.5 years. Postablation, she had 15% residual of the tumor. Since she underwent the resection, she remained stable and was weaned off carbamazepine within 1 month after the surgery. Remarkably, her weight gain stopped. The annual evaluation shows normal hypothalamic–pituitary–adrenal axis, normal insulin-like growth factor 1, secondary hypothyroidism, and stable CPP condition on treatment.

At the age of 5 years, an attempt of stopping leuprolide treatment was undertaken to test if pubertal suppression is still necessary. After 6 months of stopping treatment, the child developed progressive pubertal signs specifically Tanner III breast. Her height of 112.6 cm (79.5 percentile), weight of 27.6 kg (98.8 percentile), and body mass index of 21.7 kg/m2 (99.3 percentile). Laboratory workup revealed estradiol of 124.1 pmol/L, FSH of 6.1 IU/L, and LH of 1.13 IU/L. Therefore, we resumed treatment with leuprolide.


  Discussion Top


PHS is a rare disorder with an autosomal dominant inheritance due to GLI3 gene mutations. More than 100 cases have been reported in the medical literature with a broad phenotypic variation and variable severity.[6],[7] PHS is suspected with the presence of the following features: hypothalamic hamartoma, polydactyly (mesoaxial or postaxial), and bifid epiglottis.[3] Other associated features include craniofacial abnormalities, pituitary dysplasia and hypopituitarism, genital abnormalities, agenesis of the gallbladder, and total anomalous pulmonary venous return.[7],[8],[9] The average age of CPP presentation for females is 2.5 years (range 0.5–4 years).[5] Our case presented at the age of 3 months with thelarche followed by menarche at age 6 months, which is the earliest reported in the literature. In our case, the molecular testing was triggered by the presence of postaxial polydactyly and MRI finding consistent with a hypothalamic hamartoma.

GLI3 gene encodes a protein that has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway. This pathway is essential for early cell development, as it plays a role in cell growth, cell specialization, and the patterning of structures such as the brain and limbs. Variable phenotypes are known to be associated with GLI3 gene germline pathogenic mutation including Greig cephalopolysyndactyly syndrome (GCPS), PHS, postaxial polydactyly type A, preaxial polydactyly type IV, and acrocallosal syndrome. All described GLI3 allelic disorders are inherited in an autosomal dominant manner. Apparent genotype–phenotype correlation was reported for GLI3 genetic mutation. Frameshift variants or large deletion in the first third of GLI3 gene (5' of nt 1998 and 3' of 3481) are only known to cause GCPS. Frameshift variants in the middle third of the gene (truncations between 1998 and 3481) cause PHS and uncommonly cause GCPS. Frameshift variants in the final third of the gene (amino terminal-encoding or carboxy terminal-encoding thirds of the gene) cause GCPS, and less frequently, acrocallosal syndrome and nonsyndromic polydactyly. However, there is no apparent correlation of the variant location within gene and the severity of the phenotypes.[3],[10] Our patient has a truncating mutation in the middle third of the GLI3 gene, resulting in PHS and a phenotype consistent with PHS. These mutations are predicted to generate a constitutive repressor protein that skews the balance of activator and repressor forms of GLI3, which is a key downstream modulator of Shh signaling.

Treatment of PHS is complex and depends on the effect of the HH and the associated anomalies. Cpp is treated with gonadotropin-releasing hormone (GnRH) agonists. Surgical resection of HH is known to be effective in treating CPP. Still, surgical intervention should be preserved for patients with large hamartoma, focal neurologic and visual deficits, and intractable seizures.[5],[12] In addition, the benefits of surgical intervention for HH should outweigh the risks of postoperative complications as the need for lifelong hormonal replacement and the risk of developing diabetes insipidus. In our patient, seizures were controlled without medication, and the pituitary–hypothalamic function was preserved during postsurgical resection of HH, except that she still required continuation of treatment with GnRH agonist CPP and hypothyroidism. Early recognition of candidate patients for surgical resection of HH can lead to improved outcomes and future prognosis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Hall JG, Pallister PD, Clarren SK, Beckwith JB, Wiglesworth FW, Fraser FC, et al. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly – A new syndrome? Part I: Clinical, causal, and pathogenetic considerations. Am J Med Genet 1980;7:47-74.  Back to cited text no. 1
    
2.
Clarren SK, Alvord EC Jr., Hall JG. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly – A new syndrome? Part II: Neuropathological considerations. Am J Med Genet 1980;7:75-83.  Back to cited text no. 2
    
3.
Johnston JJ, Sapp JC, Turner JT, Amor D, Aftimos S, Aleck KA, et al. Molecular analysis expands the spectrum of phenotypes associated with GLI3 mutations. Hum Mutat 2010;31:1142-54.  Back to cited text no. 3
    
4.
Grebe TA, Clericuzio C. Autosomal dominant inheritance of hypothalamic hamartoma associated with polysyndactyly: Heterogeneity or variable expressivity? Am J Med Genet 1996;66:129-37.  Back to cited text no. 4
    
5.
Harrison VS, Oatman O, Kerrigan JF. Hypothalamic hamartoma with epilepsy: Review of endocrine comorbidity. Epilepsia 2017;58 Suppl 2:50-9.  Back to cited text no. 5
    
6.
Démurger F, Ichkou A, Mougou-Zerelli S, Le Merrer M, Goudefroye G, Delezoide AL, et al. New insights into genotype-phenotype correlation for GLI3 mutations. Eur J Hum Genet 2015;23:92-102.  Back to cited text no. 6
    
7.
Kuo JS, Casey SO, Thompson L, Truwit CL. Pallister-Hall syndrome: Clinical and MR features. AJNR Am J Neuroradiol 1999;20:1839-41.  Back to cited text no. 7
    
8.
Ito S, Kitazawa R, Haraguchi R, Kondo T, Ouchi A, Ueda Y, et al. Novel GLI3 variant causing overlapped Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS) phenotype with agenesis of gallbladder and pancreas. Diagn Pathol 2018;13:1.  Back to cited text no. 8
    
9.
Ochiai M, Nagata H, Tanaka K, Ihara K, Ohga S. Critical association of Pallister-Hall syndrome and congenital heart disease. Pediatr Int 2019;61:827-8.  Back to cited text no. 9
    
10.
Biesecker LG, Johnston JJ. Greig. Cephalopolysyndactyly syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Gripp KW, et al., editors. GeneReviews®. Seattle: Seattle Univ Washington; 1993-2021.  Back to cited text no. 10
    
11.
Nguyen D, Singh S, Zaatreh M, Novotny E, Levy S, Testa F, et al. Hypothalamic hamartomas: Seven cases and review of the literature. Epilepsy Behav 2003;4:246-58.  Back to cited text no. 11
    
12.
Biesecker LG. Pallister-Hall syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2022.  Back to cited text no. 12
    


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