Idiopathic Hypogonadotropic Hypogonadism with a Rare Hemi-Arrhinia: A Case Report with Nasal Reconstruction

Abstract

Importance

Idiopathic hypogonadotropic hypogonadism (IHH) associated with congenital hemi-arrhinia is rare but can substantially impact patients’ quality of life. The underlying genetic etiology remains to be clarified, and surgical approaches for reconstructing congenital hemi-arrhinia are sparsely reported.

Objective

To provide a reference for clinical diagnosis and management by reporting the patient’s genetic findings and surgical outcomes.

Design

Case report.

Setting

Tertiary public referral hospital.

Participants

A patient diagnosed with IHH and congenital hemi-arrhinia.

Intervention or Exposures

Whole-exome sequencing was performed, and the patient’s nose was reconstructed using the contralateral nasal dorsum flap as the inner lining, an L-strut of rib and costal cartilage graft as the structural support, and a pre-expanded forehead flap as the outer skin envelope.

Main Outcome Measures

One-year postoperative outcomes were evaluated using the Rhinoplasty Outcome Evaluation (ROE) and Nasal Obstruction Symptom Evaluation (NOSE) scales.

Results

Whole-exome sequencing revealed maternally and paternally inherited missense mutations in Gonadotropin-Releasing Hormone Receptor (GNRHR) (c.719G > A) and KISS1 (c.58G > A), respectively. One-year follow-up demonstrated stable nasal reconstruction, with the ROE score improving from 4 to 17 out of 24. The NOSE score remained 1 out of 20 pre- and postoperatively, indicating no significant change in nasal airflow perception.

Conclusions

The 4-stage surgical procedure is a viable and effective reconstructive option for hemi-arrhinia.

Relevance

Our genetic findings may serve as a reference for investigating the underlying causes of IHH. The described surgical approach provides a practical reference for surgeons performing hemi-nose reconstruction.

Graphical Abstract

Key Message

• The clinical manifestations of reproductive system developmental abnormalities and hemi-arrhinia may result from a digenic inheritance mechanism involving missense mutations in GNRHR (c.719G > A) and KISS1 (c.58G > A).

• The 4-stage procedure is a safe and effective approach for hemi-arrhinia reconstruction, providing satisfactory cosmetic outcomes while preserving nasal airflow.

Background

Idiopathic hypogonadotropic hypogonadism (IHH) is a group of genetically and phenotypically heterogeneous disorders. Because of the abnormal function of the hypothalamic Gonadotropin-Releasing Hormone (GnRH)-pituitary-gonadal axis, patients often present with aberrant genital development and absence of secondary sexual characteristics (eg, no breast development in girls, no beard and body hair development in boys). Several congenital abnormalities, including anosmia, cleft lip and palate, dental agenesis, renal defects, and limb malformations, can also be discovered, along with various gene mutations. ¹ IHH is referred to as Kallmann syndrome when anosmia or hyposmia is present, and as normosmic IHH (nIHH) when there are no olfactory abnormalities. ² More than 30 genes (GnRH receptor [GNRHR], KISS1/KISS1R, TAC3/TACR3, LEP/LEPR, PCSK1, KAL1, PROK2/PROKR2, FGFR1, FGF8, CDH7, etc.) have been identified as being associated with IHH, which is inherited in an autosomal dominant, autosomal recessive, X-linked, or oligogenic manner. ³ In excess of 50% of cases, however, a genetic cause has not been identified.

Recent research has demonstrated that patients with arrhinia frequently exhibit IHH symptoms or diseases. ⁴ Arrhinia is an extremely uncommon congenital malformation that is typically categorized as total arrhinia, hemi-arrhinia, and proboscis lateralis. ⁵ The incidence of congenital hemi-arrhinia is unknown, and fewer than 100 cases have been reported to date in the English-language literature.^{6 -9} It has been proposed that hemi-arrhinia may result from either unilateral nasal placode deficiency or failure of fusion between the medial and lateral nasal processes during embryonic development. ¹⁰ Usually, hemi-arrhinia patients have normal respiratory function, and the surgical focus is on reconstructing their appearance. Considering the numerous influencing factors, such as the timing of nasal reconstruction, the type of tissue to be used, and the method of structural construction, there are no standard operating procedures. Various surgical protocols have been described and presented with varying degrees of efficacy.

The aim of this article is to present an unusual case of IHH with hemi-arrhinia, analyze the association between the 2 diseases, share personal experience in half-nose reconstruction, and review the literature in order to compare it to other approaches.

Case Presentation

In 2020, an 18-year-old male with hemi-arrhinia presented to the plastic and reconstructive surgery department of our hospital. His parents are both Chinese and non-consanguineous, and neither has any similar congenital malformations. The mother denied taking any medication or having any infections during pregnancy. The patient’s physical examination revealed a normal left nasal sidewall, ala, and columella, and the absence of the entire right hemi-nose. However, assessments of odor threshold, odor discrimination, and odor identification indicated no olfactory dysfunction. A scar remained on the midface as a result of the surgical procedure performed at the age of 1 to repair the cleft lip (Figure 1A-C). In addition, we discovered that he has a juvenile penis, dysplastic testes, and sparse pubic hair, with no secondary sexual characteristics developing (Tanner stage G1P2).

Figure 1.

(A-C) The frontal, lateral oblique, and basal preoperative views of the patient. (D) The coronal cross-section of the preoperative cranio-maxillofacial MRI revealed the structures of the OB and OS. (E) The cross-sectional image of the preoperative CT showed that his facial bone structure was asymmetric and chaotic. (F) Three-dimensional reconstruction of CT scan provided clearer visualization of facial clefts and the left unilateral piriform aperture. (G) Pedigrees of patient with confirmed mutations. CT, Computed tomography; MRI, Magnetic resonance imaging; OB, Olfactory bulb; OS, Olfactory sulcus.

The laboratory results demonstrated that the serum concentrations of Luteinizing Hormone (0.09 mIU/mL), Follicle-Stimulating Hormone (0.25 mIU/mL), and testosterone (0.19 ng/mL) were significantly below the normal range. Other tests of anterior pituitary function, including thyroid hormones, thyroid-stimulating hormone, growth hormone, prolactin, estrogen, progestin, adrenocorticotropic hormone, and cortisol value, were within the normal range. The hypothalamus and pituitary region appeared normal on a magnetic resonance imaging (MRI) scan of the brain. The MRI images demonstrated the presence of the olfactory bulb and olfactory sulcus on the left side; however, these structures were absent on the right side (Figure 1D). The maxillofacial plain computed tomography and 3D reconstruction revealed a cleft extending obliquely upward from the alveolar groove to the maxilla, nasal septum deviation, partial loss of the septal cartilage, a left unilateral piriform aperture with unilateral ethmoid and sphenoid sinuses, and partial absence of the right nasal turbinate (Figure 1E-F and Figure S1).

The patient was ultimately diagnosed with IHH due to the absence of sexual maturation, selectively low gonadotropin, low testosterone, and normal pituitary structure.

To confirm the genetic basis of IHH in this patient, we performed whole-exome sequencing (WES) on both the patient and his parents. First, GNRHR (c.719G > A, p.R240Q) was identified as a potential disease-causing variant because it has been classified as likely pathogenic in accordance with the American College of Medical Genetics guidelines. GNRHR was known as the first gene to be identified as a monogenic cause of IHH, ¹¹ and the same heterozygous p.R240Q rare sequencing variant (RSV) had previously been reported in 4 IHH patients. ¹² However, the heterozygous RSV was inadequate to explain the clinical manifestations of IHH syndrome; patients typically carried additional variants in IHH causal or candidate genes. Therefore, we screened over 30 pathogenic genes ¹³ associated with IHH and excluded low-frequency deleterious variants. Subsequently, we identified another missense mutation in KISS1 (c.58G > A), which may represent the underlying pathogenic mutation. This patient was confirmed to have inherited the GNRHR (c.719G > A, p.R240Q) and KISS1 (c.58G > A, p.E20K) genes from his mother and father, respectively (Figure 1G). The combined effect of these 2 heterozygous mutations may have contributed to the patient’s clinical manifestations.

Prior to this, he had never received hormone replacement therapy; however, in anticipation of college life, he decided to undergo nasal reconstruction surgery out of concern for potential social communication impairments.

Surgical Technique

Nasal reconstruction usually consists of 3 components: the internal lining, structural support, and external envelope. Reconstruction in this patient involved a 4-stage procedure.

At stage Ⅰ, a 100 mL soft-tissue expander was implanted in the forehead through a horizontal incision within the hairline. The expander was then gradually inflated with 250 mL of normal saline within 3 months until the expanded flap was large enough to resurface his nose (Figure 2A).

Figure 2.

The surgical procedure for nasal reconstruction. (A) The patient following the first-stage of forehead skin expansion and the second-stage of flap delay. (B) Preoperative marking of the surgical incision line. (C) The internal lining was formed by inverting the contralateral flap. (D-E) Schematic of the process of constructing the support structure. (F) A titanium plate was used to attach the graft to the nasal bone. (G) Cartilage grafts were articulated with the underlying structure. (H) Immediate appearance following forehead flap transfer.

During stage Ⅱ, a flap delay procedure was performed on the nasal flap. The incision was made along the left nasofacial groove and the nasal alar margin, followed by dissection above the deep fascia to sever the blood supply at the base. The flap was then elevated closer to the midline while preserving the blood supply of the central zone. Subsequently, the flap was sutured back in place to allow for a 2-week period of vascular remodeling (Figure S2).

In stage III of the surgical procedure, we sequentially constructed the lining, support framework, and external cover, thereby completing the full nasal reconstruction.

• Step 1: The left nasal dorsum flap was inverted to serve as the lining for the right side. A line drawn from the central mark at the base of the columella (o point) to the midpoint between the medial canthi (o’ point) was used as the facial midline. The contour of the right hemi-nose was symmetrically delineated with a solid line based on the left side, with the corresponding medial (a’ point) and lateral (b’ point) bases of the right ala marked according to the left side’s medial (a point) and lateral (b point) landmarks. An incision was made along the right contour line, and the epidermis within the shaded area was excised to create a gap. The left nasal flap was then elevated along the incision line, inverted, and inserted into the gap. The external soft tissue and internal skin were sutured separately, forming a cylindrical structure. In addition, a small triangular flap was designed for the right nasal ala. The flap was cut along the a’c and dc axes, then raised around the a’d axis (Figure 2B). A small portion of the epidermis of the lining was excised, and the dc axis was sutured to it, forming a rounded nasal aperture (Figure 2C).

• Step 2: The structural support was reconstructed using a rib-cartilage composite (Figure 2D-E). Separate 4.5 cm segments of autologous rib bone and costal cartilage were harvested from the seventh rib. Initially, the rib was utilized to create an L-shaped bony support framework. The rib was sectioned into a 4.5 cm piece for the nasal dorsum and a 0.5 cm piece for the columella. The nasal tip end of the dorsal support was sculpted into a triangular convex shape, while the nasal root end was thinned and connected to the underdeveloped nasal bone using a titanium plate. The base of the columellar support was inserted between the medial crura and sutured to the maxillary crest, while the nasal tip end was sculpted into a triangular concave shape. The 2 bony grafts formed a mortise-and-tenon joint through their concave and convex surfaces and were secured with 4-0 Polydioxanone sutures sutures to establish a stable L-shaped support structure (Figure 2F). Subsequently, costal cartilage was used for further refinement. The 4.5 cm segment of harvested costal cartilage was sculpted into a graft with a thin nasal dorsum and a protruding nasal tip, which was then sutured to the bony framework. The remaining rib cartilage was finely trimmed into thin sheets, with 2 or 3 sheets attached to the inner lining and nasal tip cartilage on each side to reconstruct the alar structure bilaterally (Figure 2G).

• Step 3: A paramedian forehead flap with a pedicle was rotated to cover the defect. The pre-expanded forehead flap was raised based on the right supratrochlear vessel pedicle, identified by Doppler ultrasound. The flap design, consisting of 1 stem and 3 lobules, was tailored to the shape of the nose and the course of the supratrochlear artery. The forehead flap was then rotated to resurface the nasal defect. After excising an appropriate amount of subcutaneous fat from the distal portion of the flap, layered closure was performed (Figure 2H).In stage Ⅳ, the pedicle was divided 2 weeks after the flap transfer. Prior to flap inset, the proximal flap was thinned, and the nasal contour was reshaped.

Following the surgical procedures, the flaps survived without any short-term complications. During the 1-year follow-up, there was no migration or loosening of the support structure (Figure 3A-C). The patient expressed satisfaction with the postoperative results, as evidenced by an increase in the Rhinoplasty Outcome Evaluation score from 4 points preoperatively to 17 points postoperatively, out of a possible 24 points (Table S1). In addition, both the preoperative and postoperative Nasal Obstruction Symptom Evaluation (NOSE) scale scores remained constant at 1 out of 20, suggesting no significant change in respiratory perception (Table S2). Due to postoperative scarring and contracture, the patient received intralesional injection of corticosteroids and 5-fluorouracil to prevent scar hyperplasia. Next, he was referred to the endocrinology department for further treatment of IHH.

Figure 3.

The 1-year postoperative follow-up results. (A-C) The frontal, lateral oblique, and basal postoperative views of the patient.

Discussion

IHH exhibits genetic heterogeneity, with over 30 genes identified as being associated with the condition. ¹³ The inheritance can vary, with oligogenic inheritance potentially being responsible for the vast majority of cases. In addition, the penetrance and expressivity of the gene can vary, leading to some affected family members not exhibiting any symptoms. In our case, each parent carried a heterozygous mutation, 1 in GNRHR (p.R240Q) and the other in KISS1 (p.E20K), without any clinical manifestations. In contrast, the patient, who carried both heterozygous mutations, presents with multiple reproductive and non-reproductive phenotypes. Thus, we speculate that the combined presence of heterozygous mutations in GNRHR and KISS1 contributes to the development of disease via a digenic inheritance mechanism. GNRHR is the first gene to be identified as a monogenic cause of IHH. ¹¹ To date, over 50 natural loss-of-function GNRHR mutations (single nucleotide variants and frameshift) have been reported in the literature. ¹⁴ Different mutation sites showed heterogeneity by affecting protein structure and function in distinct manners. ¹⁵ According to the functional analysis, the RSV (p.R240Q) caused a partial loss of function in the GNRHR protein. ¹² The patients carrying heterozygous RSV (p.R240Q) in GNRHR exhibited varying degrees of testicular development and hormone profile severity. The pathogenicity of this RSV may be less severe for the GNRHR protein, and the heterozygous state may only have a minimal impact on disease development. Patients with GNRHR RSV typically have additional genetic abnormalities, including the known IHH causal genes PROKR2, SEMA7A, AXL, RSVPs, and so on. Mutations in the KISS1gene, which encodes kisspeptins that affect the depolarization of GnRH neurons and stimulate GnRH release, were also found in our patient. ¹⁶ We speculate that loss of KISS1 function leads to reduced GnRH secretion and subsequent decreased activation of GnRHR, which, together with the functional impairment caused by the GNRHR mutation, synergistically exacerbates downstream dysfunction of the GnRH/GnRHR signaling pathway.

However, WES is unable to explain the cause of the arrhinias. From the perspective of embryonic development, GnRH neurons migrate through the nasal region along olfactory axons, which may explain why anosmia often coexists with IHH. ² Prior to 2017, only 3 males and 1 female were reported to have IHH along with arrhinias.^15,16 In 2020, Delaney et al evaluated the reproductive function of 51 arrhinia patients and found that, with the exception of 2 females, all of them exhibited inhibitive reproduction. ⁴ The correlation between arrhinia and IHH is much stronger than previously thought. To our knowledge, this is the only reported case of an IHH patient with hemi-arrhinia but without anosmia. The hemi-arrhinia deformity may be caused by an underdeveloped placode on 1 side, an incomplete fusion of the lateral nasal processes and the maxillary processes, or other factors. ¹⁰ The absence of half-nose may be attributable to a decrease in GnRH neurons that promote the development of IHH symptoms. Overall, the underlying mechanisms are poorly understood, but we should pay more attention to the reproductive development of young hemi-arrhinia patients in order to initiate early endocrine therapy.

After conducting a literature review on the subject, we discovered fewer than 100 reported cases of hemi-arrhinia.^{6 -9} Not all cases were surgically treated due to the unaffected respiratory function and refusal of some patients for financial reasons. In general, previous surgical strategies can be categorized into half-nose and total nasal reconstruction. Initially, attempts were made to reconstruct the half nose using expanded forehead tissue and a nasolabial flap as the covering and lining, respectively, resulting in an obvious scar along the midline.^{17 -19} To avoid a conspicuous midline scar, plastic surgeons elevated the native nasal skin at the defect site as a local in situ flap to serve as the external cover. However, postoperative retractions and collapses of the constructed hemi-noses were common.^6,9,20 Bryant incorporated a rib-cartilage scaffold into the regional flap to provide structural support; however, significant alar retrusion remained inevitable. ⁸ After attempting to reconstruct only the affected side with a local mucosal and forehead flap and observing poor morphology, Renato et al. presented their standard approach for overall nasal reconstruction: a triple-layer structure composed of contralateral cutaneous nasal flap, forehead skin, and ear tragus cartilage. Long-term effects were not evaluated in this case series, but a short-term follow-up revealed significant scarring on the forehead and a swollen nasal shape. ¹⁰ Later, Dr. Prada reported a patient who was reconstructed with a pre-expanded forehead flap, resulting in a favorable outcome and stable morphology over a 10-year period of observation. ²¹

According to previous reports and experience, we believe that a comprehensive reconstruction may be the best option, with a structurally stable scaffold required. We selected the contralateral nasal flap, ribs with costal cartilages, and forehead pre-expanded flap as the inner lining, structural support, and covering, respectively. The following are some key features of our design:

1. The lining replaced by the contralateral flap was symmetrical and will not result in an additional lesion at the donor site. Mucosal flaps are typically necessary for nasal reconstruction in order to rebuild the inner lining for its humidification function, ²² but this is not the case in patients with hemi-arrhinia. Respiratory function is typically normal in patients with hemi-arrhinia, so the emphasis is on reconstructing the patient’s appearance, with the optimal choice being a readily available contralateral nasal flap that does not cause additional impairment, followed by delayed surgery to ensure flap survival.

2. The use of a triangular alar flap to prevent alar retraction. Alar retraction is 1 of the most common complications in nasal reconstruction. Based on our long-term clinical experience, the flipped triangle flap could exert a downward force on the alar rim, thereby reducing the tendency toward alar retraction. Similar results were observed in our patients who underwent nasal reconstructive surgery using this flap design.

3. The pre-expanded flap was generally thinner, which contributed to its plasticity and resulted in a narrower scar on the forehead. The forehead flap is considered the gold standard due to its similarity in color, texture, and proximity. Giugliano et al ²³ suggested that tissue expansion should only be used in cases with small donor sites because the expanded flap may contract in the postoperative period, resulting in a short nose in the long run. However, we are more inclined to use the pre-expanded forehead flap, which is thin and leaves a narrower scar at the donor site. The risk of flap contraction can be decreased by keeping the flap size slightly larger than the defect site and constructing a solid scaffold during operation.

4. The bony support structure achieved outstanding stability due to the L-strut of a mortise-and-tenon joint and fixation with a titanium miniplate. For structural support, autologous tissues are most commonly used. Bone grafts are typically used to reconstruct midline structures due to their superior support capacity. The most common free bone grafts are the split calvaria bone and rib. ²² Our bony L-strut of a mortise-and-tenon joint was fixed to the remnant woven bone using a titanium plate, which provided the height of the dorsum and a stable structural foundation.

5. The use of rib in conjunction with costal cartilage improved the height and texture of the reconstructed nose. Although costal cartilage is commonly used as a structural graft in nasal reconstruction due to its favorable texture and ease of carving, its limited mechanical strength is associated with a higher risk of warping and resorption.^24,25 Accordingly, in our approach, rib grafts were employed to establish a stable midline framework, providing robust structural support. Cartilage grafts were then secured onto the rib framework to augment the nasal dorsum, refine the nasal tip contour, and enhance the overall nasal morphology.

6. Alar deformation may be avoided through the splicing of multiple pieces of cartilage as opposed to a single large bulk of cartilage. Costal cartilage is frequently employed in rhinoplasty and nasal reconstruction; however, postoperative curvature remains a prevalent complication. ²⁶ This issue arises because costal cartilage contributes to thoracic elasticity by connecting the ribs to the sternum, and its intrinsic growth pattern is curved. ²⁷ Upon transplantation from its original mechanical environment to the nasal ala, the entire cartilage graft experiences great tension, leading to deformation over time and challenges in maintaining long-term morphological stability. ²⁸ By splicing the cartilages and suturing to the lining, the ala can be effectively shaped with minimal tension, thereby reducing the potential for elastic deformation typically associated with the use of the entire cartilage.

The timing of nasal reconstruction in patients with hemi-arrhinia remains controversial. Some argue that, from both cosmetic and psychological standpoints, surgical intervention should be performed as soon as possible. On the other hand, many authors recommend delaying the surgery until at least preschool years. Some also suggest that the optimal time would be after the completion of facial development. ⁶ In our opinion, a staged surgical strategy may be a reasonable solution. In preschool-aged patients, an initial limited reconstruction, such as nostril creation using an ipsilateral nasolabial flap, may be performed for early aesthetic improvement. The forehead flap is deliberately preserved at this stage to allow definitive nasal reconstruction after completion of facial growth. Once adulthood is reached, a 4-stage forehead flap–based reconstruction can then be performed. In our case, the patient had already reached the age of 18 years old at the initial visit. Therefore, we adopted this 1-shot approach for overall reconstruction.

Conclusion

The 4-stage surgical procedure is an effective reconstructive choice for hemi-arrhinia, with desirable outcomes.

Supplemental Material

sj-docx-1-ohn-10.1177_19160216261425177 – Supplemental material for Idiopathic Hypogonadotropic Hypogonadism with a Rare Hemi-Arrhinia: A Case Report with Nasal Reconstruction

Supplemental material, sj-docx-1-ohn-10.1177_19160216261425177 for Idiopathic Hypogonadotropic Hypogonadism with a Rare Hemi-Arrhinia: A Case Report with Nasal Reconstruction by Yunhan Liu, Yimin Khoong, Xin Huang, Shuchen Gu and Tao Zan in Journal of Otolaryngology - Head & Neck Surgery