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 Table of Contents  
CASE REPORT
Year : 2022  |  Volume : 9  |  Issue : 2  |  Page : 180-183

A case of idiopathic hypogonadotropic hypogonadism with dental and orofacial defects: A key to the perception of possible molecular etiology


1 Departments of Dentistry (Oral and Maxillofacial Surgery), All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
2 Departments of Pediatrics, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
3 GSR Institute of Cranio-Maxillofacial and Facial Plastic Surgery, Hyderabad, Telangana, India

Date of Submission19-Mar-2022
Date of Acceptance16-Apr-2022
Date of Web Publication23-Aug-2022

Correspondence Address:
Dr. Prashant Kumar Verma
Department of Pediatrics, All India Institute of Medical Sciences, Rishikesh - 249 203, Uttarakhand
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jclpca.jclpca_7_22

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  Abstract 


Isolated deficiency of gonadotropin-releasing hormone is a heterogeneous disorder with wide genetic and clinical overlap. It mainly presents as hypogonadotropic hypogonadism (HH). HH associated with anosmia is known as Kallmann syndrome (KS), while its normosmic variant is called normosmic idiopathic HH. However, it is associated with several nonreproductive features including dental defects. Fibroblast growth factor receptor 1 gene mutation, which is seen in the autosomal dominant form of idiopathic HH (HH 2), has often been linked to the associated dental abnormalities and orofacial defects; however, no literature exists for its association with anosmin-1 (ANOS1) gene mutation which is found in the X-linked form of HH (KS). ANOS1 gene was earlier known as KAL1 (Kallmann syndrome 1) gene, and encodes for the extracellular matrix protein called anosmin. Hence, we report a case of idiopathic HH (KS) so as to delineate the possible role of ANOS1 gene in dental/orofacial development. This can help prioritize gene screening and also provide scope for further genetic studies required to prove such association.

Keywords: Anosmin-1, bimanual synkinesis, fibroblast growth factor receptor 1, hypogonadotropic hypogonadism, Kallmann syndrome


How to cite this article:
Bansal A, Verma PK, Bhakat R, Chug A, Reddy SG. A case of idiopathic hypogonadotropic hypogonadism with dental and orofacial defects: A key to the perception of possible molecular etiology. J Cleft Lip Palate Craniofac Anomal 2022;9:180-3

How to cite this URL:
Bansal A, Verma PK, Bhakat R, Chug A, Reddy SG. A case of idiopathic hypogonadotropic hypogonadism with dental and orofacial defects: A key to the perception of possible molecular etiology. J Cleft Lip Palate Craniofac Anomal [serial online] 2022 [cited 2022 Dec 8];9:180-3. Available from: https://www.jclpca.org/text.asp?2022/9/2/180/354298




  Introduction Top


Isolated deficiency of gonadotropin-releasing hormone (GnRH) is a heterogeneous disorder with a wide range of genetic and clinical overlap. Its most important aspect is represented by hypogonadotropic hypogonadism (HH) with or without anosmia, and delayed pubertal development. However, it is associated with several nonreproductive features such as cleft lip/palate, dental defects, abnormalities of bone, renal agenesis, synkinesis, loss of hearing, and impaired balance due to cerebellar abnormality. Genetic mutations explain about 40% of HH cases in literature and the rest are uncharacterized.[1] Dental abnormalities and orofacial defects have usually been associated with fibroblast growth factor receptor 1 (FGFR1) gene mutation in HH; however, there is no literature supporting the association of anosmin-1 (ANOS1)/KAL1 gene mutation with the same. Hence, we report a case of idiopathic HH (Kallmann syndrome) so as to delineate the possible role of ANOS1 gene in dental/orofacial development, which might help prioritize the required genetic screening.


  Case Report Top


A 14-year-old male patient reported with a complaint of small-sized penis and enlargement of breast tissue. There was no history of delayed growth spurt or traumatic injury. No abnormal features could be discerned from parents. Furthermore, no significant medical or prolonged drug intake history was reported. Vitals and stature (height: 151 cm) were within the normal limits. Facial examination revealed asymmetry, with the right ear (7 cm) being greater in length than the left ear (6.5 cm), along with dental malocclusion [Figure 1] and high-arched palate [Figure 2]. Bilateral gynecomastia was evident with nonpalpable glandular tissue [Figure 3]; along with absent pubic, facial, and axillary hair. The right testis was nonpalpable, while the left testis was palpable in the scrotum, with the testicular volume of <4 ml, thus corresponding to Tanner Stage I (Sexual Maturity Rating). Stretched penile length was 5 cm [Figure 4]. Asymmetrical partial anosmia (right > left) was present, along with positive bimanual synkinesis. Blood chemistry revealed decreased levels of testosterone (20.34 ng/dL, range: 270–1070 ng/dL), luteinizing hormone (0.01 mIU/mL, range: 1.50–9.30 mIU/mL), and follicular-stimulating hormone (0.02 mIU/mL, range: 1.40–18.10 mIU/mL). GnRH analog (Leupride) stimulation test revealed minimal response indicative of GnRH deficiency. Inhibin values were significantly low (23.14 pg/mL, range: 169–216 pg/mL).
Figure 1: Dental malocclusion associated with the case

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Figure 2: Associated high-arched palate

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Figure 3: Evident bilateral gynecomastia with nonpalpable glandular tissue

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Figure 4: Stretched penile length which was found to be 5 cm

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X-ray wrist and pelvis estimated bone age to be 12–14 years which were equivalent to the chronological age. Ultrasound of the kidney, urinary bladder, and scrotum (USG KUB) revealed right ureterocele and small right kidney (4.2 cm × 3.6 cm) suggestive of renal dysplasia, along with normal left kidney (9.2 cm × 3.5 cm). Furthermore, the right testis was absent in the scrotum. The right renal dysplasia was confirmed in magnetic resonance imaging (MRI) abdomen and pelvis, along with absent right seminal vesicle. The right kidney could not be visualized in dimercaptosuccinic acid scan. A micturating cystourethrogram showed no vesicoureteral reflux. MRI brain depicted partial empty sella. The above positive clinical features and investigations were consistent with HH 1 with partial anosmia or Kallmann syndrome (KS) as shown in [Table 1], but the diagnosis could not be confirmed as genetic study could not be undertaken due to financial constraints of the family. The patient responded well to hormone replacement therapy (HRT).
Table 1: Phenotypic series of hypogonadotropic hypogonadism along with its characteristic features as per OMIM database search

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  Discussion Top


Isolated GnRH deficiency (IGD) includes a wide spectrum of disorders. It shows male predominance, with an incidence of 1:30,000 in males and 1:125,000 in females.[2] IGD mainly presents as HH, which has 25 phenotypic variants as per Online Mendelian Inheritance in Man (OMIM) database search [Table 1]. HH associated with partial or complete anosmia is known as KS, while its normosmic variant is called normosmic idiopathic HH.[3] Constitutional delay of puberty, hypothalamic amenorrhea, and adult-onset HH are milder and common diseases associated with IGD.[1]

Along with reduced sense of olfaction, KS presents with decreased levels of sex hormones along with unilateral renal agenesis, delayed puberty, micropenis, ectopic testis, and bimanual synkinesis.[4] Till date, 15 genes have been found responsible for isolated HH, such as FGFR1, KAL1, NELF, FGF8, PROKR8, PROK2, WDR11, CHD7, KISS1R, KISS1, SEMA3A, TAC3, TACR3, GNRHR, and GNRH1.[5] Several genes act as “overlap genes” which are involved in both neuroendocrine and neurodevelopmental pathogenetic pathway, and thus play as “second hits” explaining their variable expressions and incomplete mode of penetrance.[1]

KAL1 (Kallmann syndrome 1) gene, which is now known as ANOS1 gene has been identified for X-linked form of HH, i.e., KS, while FGFR1 gene has been associated with its autosomal dominant form, i.e., HH 2.[6] Heterozygous mutations in FGFR1 account for 10% of HH two patients, and they occasionally feature characteristic dental agenesis/malocclusion, midline defects such as cleft lip and palate, and high-arched palate.[6] Massin N et al. also identified heterozygous missense mutation in FGFR1 or KISS1R responsible for such orofacial defects.[7] However, no literature exists for its association with ANOS1 gene mutation.

ANOS1 gene encodes the extracellular matrix protein called anosmin. It is implicated in fibroblast growth factor (FGF) signaling and enhancement of FGF8 functions and hence is required for the formation of the neural crest cells of cranium by modulating growth factors.[8] Thus, its mutation can cause imbalance in embryonic development including the development of dentition and morphology of craniofacial region, equivalent to our case report. However, ANOS1/KAL1 gene mutation has not been ascribed to the dental and orofacial features in the X-linked form of HH, i.e., KS till date.

Chan et al. presented the first case of genetic testing of such disorders in preimplantation phase.[9] Management of such genetic disorders requires frequent family counseling due to their risk of transmission, and medically assisted management with HRT for better prognosis.[10]

KS is a genetic disorder presenting mainly with HH along with partial or complete anosmia. It has a wide and variable clinical spectrum along with different genetic patterns. FGFR1 gene mutation has often been linked to its associated dental and orofacial defects. However, this is the first case report giving an insight toward the possible role of ANOS1 gene toward such development. This can help us prioritize particular gene screening and also provides scope for further genetic studies required to prove such association.

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 initial s 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.
Stamou MI, Georgopoulos NA. Kallmann syndrome: Phenotype and genotype of hypogonadotropic hypogonadism. Metabolism 2018;86:124-34.  Back to cited text no. 1
    
2.
Laitinen EM, Vaaralahti K, Tommiska J, Eklund E, Tervaniemi M, Valanne L, et al. Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland. Orphanet J Rare Dis 2011;6:41.  Back to cited text no. 2
    
3.
Topaloğlu AK. Update on the genetics of idiopathic hypogonadotropic hypogonadism. J Clin Res Pediatr Endocrinol 2017;9:113-22.  Back to cited text no. 3
    
4.
Roy A, Kamalanathan S, Sahoo JP, Ananthakrishnan R. Bimanual synkinesia in Kallmann's syndrome. BMJ Case Rep 2019;12:e230147.  Back to cited text no. 4
    
5.
Beate K, Joseph N, Nicolas de R, Wolfram K. Genetics of isolated hypogonadotropic hypogonadism: Role of GnRH receptor and other genes. Int J Endocrinol 2012;2012:147893.  Back to cited text no. 5
    
6.
Sato N, Ohyama K, Fukami M, Okada M, Ogata T. Kallmann syndrome: Somatic and germline mutations of the fibroblast growth factor receptor 1 gene in a mother and the son. J Clin Endocrinol Metab 2006;91:1415-8.  Back to cited text no. 6
    
7.
Massin N, Pêcheux C, Eloit C, Bensimon JL, Galey J, Kuttenn F, et al. X chromosome-linked Kallmann syndrome: Clinical heterogeneity in three siblings carrying an intragenic deletion of the KAL-1 gene. J Clin Endocrinol Metab 2003;88:2003-8.  Back to cited text no. 7
    
8.
Endo Y, Ishiwata-Endo H, Yamada KM. Extracellular matrix protein anosmin promotes neural crest formation and regulates FGF, BMP, and WNT activities. Dev Cell 2012;23:305-16.  Back to cited text no. 8
    
9.
Chan C, Wang CW, Chen CH, Chen CH. Live birth in male de novo Kallmann syndrome after cross-generational genetic sequencing. J Assist Reprod Genet 2019;36:2481-4.  Back to cited text no. 9
    
10.
Maione L, Dwyer AA, Francou B, Guiochon-Mantel A, Binart N, Bouligand J, et al. Genetics in endocrinology: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: New challenges in the era of oligogenism and next-generation sequencing. Eur J Endocrinol 2018;178:R55-80.  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

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