Familial Turner Syndrome With Distinct Karyotypes in Two Cousins: Phenotypic Convergence and Genotypic Heterogeneity

Introduction

Turner syndrome (TS), also known as congenital ovarian dysplasia syndrome, occurs in approximately 1 in 2500 to 1 in 4000 female live births [1] and represents the only viable complete monosomy in humans [2]. The pathological basis of TS is characterized by complete or partial deletion, mosaicism, or structural rearrangement of 1 X chromosome in all or some of the patient’s cell types [2]. The clinical presentation of TS includes multisystem anomalies such as short stature, craniofacial abnormalities, delayed puberty, gonadal dysfunction, infertility, and cardiac or renal malformations [1,3,4]. Delayed growth and primary gonadal dysgenesis are the most common manifestations [1,3]. Primary gonadal failure and infertility are hallmark features of TS; the condition is generally considered sporadic, rather than hereditary. Notably, rare instances of familial TS challenge the conventional paradigm of random meiotic or mitotic errors. In previously reported familial cases, affected relatives have predominantly shared identical or closely related karyotypes, often resulting from transmission of a partial X-chromosome deletion or a parental balanced translocation [5,6]. However, the occurrence of distinct TS karyotypes within the same generation of a single family is an exceptionally rare phenomenon that complicates standard models of inheritance. Such cases raise critical questions regarding potential hidden genetic predispositions to chromosomal instability or germline mosaicism.

This report describes a unique familial cluster in which 2 cousins in the same generation exhibited classic TS phenotypes but harbored discordant karyotypes: 46,X,i(X)(q10) and 45,X. Whereas prior works involved limited genetic testing, we performed comprehensive whole-exome sequencing (WES) and copy number variation (CNV) analysis across 11 family members to investigate potential heritable drivers. By analyzing the phenotypic convergence despite divergent genotypes, this report highlights the central role of X-chromosome short arm (Xp) haploinsufficiency and explores the complexities of genetic counseling when recurrence risk cannot be quantified via standard Mendelian principles.

Case Reports

FAMILY INFORMATION:

This family pedigree comprises 62 members, among whom 2 women (III-17 and III-13) were diagnosed with classical TS and had normal intelligence. Both had been born to nonconsanguineous, phenotypically normal parents without dysmorphic features, intellectual disability, or reproductive impairment. The family pedigree is illustrated in Figure 1.

Parents and siblings: The parents of both patients had short stature (III-17: father 167 cm, mother 150 cm; III-13: father 162 cm, mother 148 cm) but no delayed growth, ovarian dysfunction, or reproductive impairment. Siblings were phenotypically normal, and heights were within expected ranges (eg, III-17’s brother 169 cm; III-13’s sister 150 cm, currently 28 weeks pregnant with a normally developing fetus).

Grandmother (I-2): Height less than 150 cm; 8 offspring (6 daughters and 2 sons), no reproductive impairment. Cytogenetic analysis could not be performed because she was deceased. Although her short stature raises the possibility of low-level TS mosaicism or germline mosaicism, this interpretation remains speculative; alternative explanations such as constitutional short stature cannot be excluded.

Nephew (IV-10): Delayed growth (height 100 cm at age 4 years, −1 standard deviation) and preterm birth (32 weeks, birth weight 2.4).

CLINICAL AND PHYSICAL ASSESSMENT:

Both patients presented with primary amenorrhea, denied any history of sexual activity, and shared a history of preterm birth and low birth weight. The proband (III-17) had been born at 34 weeks (2.2 kg); her cousin (III-13) had been born at 32 weeks (1.9 kg). Physical examination revealed pronounced short stature in both patients, with heights falling well below the 3rd percentile for adult women. The proband measured 135 cm and weighed 35 kg, whereas her cousin measured 128 cm and weighed 35 kg.

Despite similar growth delay, their somatic features differed. The proband (46,X,i(X)(q10)) lacked typical TS stigmata. In contrast, her cousin (45,X) presented with classic somatic features, including a webbed neck, low posterior hairline, shield chest, and cubitus valgus. Both women exhibited infantile external genitalia. Sexual development was arrested at early Tanner stages; the proband displayed Tanner stage B2/PH2, whereas the cousin showed Tanner stage B1/PH1.

HORMONAL AND IMAGING FINDINGS:

Endocrine profiling demonstrated a convergent pattern of hypergonadotropic hypogonadism. Both patients exhibited follicle-stimulating hormone levels exceeding 40 IU/L, elevated luteinizing hormone, and low estradiol concentrations (Table 1). Progesterone, prolactin, and testosterone levels were within normal limits. Metabolic screening revealed insulin resistance in the proband (fasting insulin 736.85 pmol/L) and subclinical hypothyroidism in the cousin (thyroid-stimulating hormone 5.566 mIU/L), consistent with known TS comorbidities.

Pelvic ultrasonography confirmed genital tract abnormalities in both cousins. The proband showed a faintly visible left ovary but no distinct uterus or right ovary. The cousin demonstrated complete absence of the uterus and ovaries. Systematic screening for cardiovascular and renal anomalies, including echocardiography and renal ultrasound, produced negative results in both patients. Bone age was delayed in both women (13.5 years in the proband and 14 years in the cousin).

Key findings and a quantitative comparison of phenotypic severity are summarized in Table 1.

CHROMOSOMAL AND MOLECULAR ANALYSIS:

Peripheral blood karyotyping using G-banding confirmed distinct chromosomal abnormalities. The proband (III-17) was identified as 46,X,i(X)(q10), indicating an isochromosome of the long arm of the X chromosome (Figure 2). The cousin (III-13) was identified as 45,X, indicating complete monosomy X (Figure 3).

To investigate a potential heritable cause for this clustering, WES and CNV analyses were performed on DNA from 11 family members, including both patients, their parents, siblings, and additional available relatives. The analysis was conducted on an Illumina platform. No clinically reportable sequence variants or pathogenic CNVs were identified in unaffected relatives according to American College of Medical Genetics and Genomics 2015/2019 guidelines. The technical limitations of these assays should be noted: conventional G-band karyotyping typically resolves abnormalities of 5 to 10 Mb or greater; chromosomal microarray or CNV calling from WES reliably detects copy-number events on the order of tens to hundreds of kilobases, depending on probe or coverage density; and WES generally detects mosaicism at levels of approximately 5% to 10% for sequence variants, depending on sequencing depth and bioinformatic analysis. Consequently, low-level (less than ~5–10%), balanced or complex structural rearrangements, deep intronic variants outside exome targets, and tissue-restricted mosaicism could escape detection.

REPRODUCTIVE FOLLOW-UP:

Both patients were counseled regarding the standard of care for TS, specifically the strong recommendation for hormone replacement therapy (HRT) to induce secondary sexual characteristics and mitigate long-term cardiovascular and skeletal risks. Although financial assistance covering the costs of treatment and follow-up assessments was arranged, both patients declined to initiate HRT for personal and occupational reasons; they were unwilling to return for in-person reassessment. Neither patient reported prior exposure to growth hormone therapy. Both also clearly stated that they had no desire for childbearing and received appropriate reproductive counseling.

Structured telephone follow-up was conducted for both patients at regular intervals (every 3–6 months). To date, no significant changes in overall health status or new clinical manifestations have been reported. The importance of baseline and periodic surveillance was repeatedly emphasized, particularly in the context of deferred HRT, with the aim of encouraging treatment initiation and appropriate long-term health monitoring.

Discussion

PRINCIPAL FINDINGS AND NOVELTY OF KARYOTYPIC HETEROGENEITY:

This report documents an exceptionally rare familial clustering of TS where 2 cousins in the same generation show remarkably convergent phenotypes but carry distinct karyotypes: 46,X,i(X)(q10) and 45,X. This observation is strengthened by extended pedigree evaluation and negative WES/CNV testing across 11 relatives, reducing (but not eliminating) the likelihood of a segregating single-gene disorder or large recurrent CNV causing predisposition to TS in this family.

PHENOTYPIC CONVERGENCE ACROSS DISTINCT X-CHROMOSOME LOSSES:

Despite the chromosomal difference, the cousins displayed remarkable quantitative convergence in their core phenotypes. Both exhibited severe short stature (height standard deviation score [SDS] −4.2 vs −5.1; difference 0.9 SDS, modest effect size), profound hypergonadotropic hypogonadism with follicle-stimulating hormone levels elevated 7.6 times the upper limit of normal (ULN) in III-17 and 12.5 times ULN in III-13, suppressed estradiol, and delayed bone age (13.5 vs 14 years); concordant pelvic imaging demonstrated gonadal dysgenesis. These findings support the hypothesis that loss of Xp is the primary driver of the TS phenotype [31,32]. The proband’s isochromosome X-chromosome long arm (Xq) results in monosomy of Xp and trisomy of Xq, whereas the cousin’s 45,X karyotype produces monosomy of both arms. The similarity in their clinical presentation suggests that duplication of Xq material in the proband did not compensate for loss of Xp, nor did it substantially alter the phenotype compared with the 45,X cousin. These observations are consistent with the understanding that dosage-sensitive genes located on Xp, such as SHOX, are critical determinants of stature and skeletal development.

The cousin with 45,X displayed more classic somatic stigmata and complete absence of pelvic organs on imaging, whereas the proband with 46,X,i(X)(q10) lacked classic stigmata and displayed faint residual ovarian tissue. This pattern is consistent with clinical experience indicating that 45,X may be associated with more frequent classic stigmata; however, such a difference does not materially alter the central inference of core phenotypic convergence when Xp dosage is reduced.

PEDIGREE INTERPRETATION: SEPARATING INFERENCE FROM SPECULATION:

The mechanism underlying familial clustering with 2 distinct chromosomal errors in a single generation remains under investigation. We propose 2 primary hypotheses, although neither can be definitively proven without gametic analysis.

GERMLINE MOSAICISM: It is biologically plausible that a phenotypically normal ancestor, such as the grandmother (I-2), possessed gonadal mosaicism involving different aneuploid cell types. Such mosaicism could lead to the production of oocytes with different X-chromosome abnormalities [33]. The grandmother’s reported short stature supports this possibility, although her fertility was preserved.

COINCIDENTAL DE NOVO EVENTS:

Given the baseline population prevalence of TS (~1/2500), the occurrence of 2 independent de novo events (independent nondisjunction or mitotic errors) in a large pedigree of 62 members, although statistically unlikely, remains a plausible explanation.

Our data do not establish a heritable mechanism. The key empirical findings are: (i) discordant karyotypes in 2 cousins, (ii) no identified segregating pathogenic variant or recurrent CNV in 11 tested relatives, and (iii) absence of parental phenotypes suggestive of TS. Hypotheses such as germline mosaicism in an ancestor or increased susceptibility to X-chromosome missegregation remain speculative because parental gonadal tissue was not tested and low-level mosaicism cannot be excluded by peripheral blood assays. Accordingly, this pedigree should be interpreted as familial clustering with an uncertain mechanism, rather than proof of inheritance.

MOLECULAR TESTING RESOLUTION AND THE RESIDUAL DIAGNOSTIC GAP:

Our extensive WES and CNV analyses of 11 family members did not identify any shared pathogenic variants in genes associated with chromosomal segregation. However, the inability to test parental gonadal tissue and the limited sensitivity of current assays for detecting balanced rearrangements or low-level somatic mosaicism preclude definitive exclusion of a cryptic familial predisposition. Moreover, typical TS etiologies, such as meiotic or mitotic errors, may not leave a detectable exomic signature. Where available, chromosomal microarray analysis and targeted fluorescence in situ hybridization can provide additional value in suspected mosaicism or cryptic structural abnormalities; long-read sequencing approaches may clarify complex X-chromosome rearrangements. However, even enhanced testing may not fully eliminate uncertainty regarding recurrence risk in families with clustering.

CLINICAL AND COUNSELING IMPLICATIONS ANCHORED TO THIS FAMILY:

For clinicians and genetic counselors, the practical lesson is not that familial TS is “inherited,” but that TS can cluster in families with unexpected genetic heterogeneity; negative family-wide genomic testing does not eliminate counseling uncertainty. In such contexts, counseling should emphasize the following:

In the absence of an identifiable heritable rearrangement (such as a parental balanced translocation), counseling should explicitly state that recurrence risk may be higher than the general population baseline (~1/2500) but remains uncertain and cannot be precisely quantified. Individualized recurrence-risk discussions must acknowledge this uncertainty.

Counseling should emphasize phenotypic variability and karyotypic heterogeneity among affected relatives and recommend comprehensive cytogenetic evaluation for at-risk family members. Prenatal diagnosis should include broad screening for X-chromosome abnormalities (eg, noninvasive prenatal screening with confirmatory diagnostic testing when indicated), rather than targeted testing for a specific karyotype.

Careful psychosocial counseling regarding fertility, HRT, and long-term surveillance should also be provided.

LIMITATIONS AND IMPLICATIONS:

We highlight several limitations that materially affect mechanistic inference and recurrence-risk counseling:

These limitations directly constrain mechanistic conclusions and support a cautious approach to counseling.

Conclusions

This case provides several practice-oriented insights that are directly applicable to clinical and genetic counseling settings:

Overall, this case of familial TS with distinct karyotypes underscores the complexity of X-chromosome inheritance and highlights – for clinicians and genetic counselors – the importance of cautious interpretation, comprehensive genetic counseling, and further investigation in similarly affected families.