Clinical characteristics.

X-linked acrogigantism is the occurrence of pituitary gigantism in an individual heterozygous or hemizygous for a germline or somatic duplication of GPR101. X-linked acrogigantism is characterized by acceleration of linear growth in early childhood – in most cases during the first two years of life – due to growth hormone (GH) excess. Most individuals with X-linked acrogigantism present with associated hyperprolactinemia due to a mixed GH- and prolactin-secreting pituitary adenoma with or without associated hyperplasia; less commonly they develop diffuse hyperplasia of the GH- and prolactin-secreting pituitary cells without a pituitary adenoma. Most affected individuals are females. Growth acceleration is the main presenting feature; other frequently observed clinical features include enlargement of hands and feet, coarsening of the facial features, and increased appetite. Neurologic signs or symptoms are rarely present. Untreated X-linked acrogigantism can lead to markedly increased stature, with obvious severe physical and psychological sequelae.

Diagnosis/testing.

The diagnosis of X-linked acrogigantism is established in an individual with pituitary gigantism and a germline or somatic duplication of GPR101 identified by molecular genetic testing.

Management.

Treatment of manifestations:

• In patients with radiologic evidence of a pituitary adenoma: transsphenoidal surgery should be considered as first-line treatment as it can provide long-term control of the disease (although often at the cost of permanent hypopituitarism) and prevent excessive tumor growth; in those with persistent disease, GH receptor antagonist treatment should be promptly initiated and tailored to growth velocity and IGF-1 levels.
• In patients with radiologic evidence of hyperplasia without a pituitary tumor: first-line treatment with GH receptor antagonist should be considered as surgery (which is not usually recommended) can lead to disease remission only by means of a total hypophysectomy, invariably resulting in the need for lifelong pituitary hormone replacement treatment.
• In patients with associated hyperprolactinemia: a dopamine agonist should be employed.

Surveillance: Intensive monitoring of height, growth velocity, and pituitary function tests. Repeat pituitary MRI (with frequency based on presence of hyperplasia/tumor, previous extent of the tumor, treatment modality, clinical status, and disease activity). Routine surveillance for complications of GH excess (based on recommendations for patients with acromegaly).

Genetic counseling.

X-linked acrogigantism is inherited in an X-linked manner. The majority of affected individuals represent simplex cases (i.e., a single occurrence in a family) resulting from a de novo GPR101 duplication; of note, all males who are simplex cases have had a somatic mosaic GPR101 duplication. In the three reported instances of familial X-linked acrogigantism, affected males inherited the GPR101 duplication from their affected mothers. Females with X-linked acrogigantism have a 50% chance of transmitting the GPR101 duplication in each pregnancy. While a male with a somatic mosaic GPR101 duplication that involves germ cells could theoretically transmit the duplication to his daughters, and a male with a germline GPR101 duplication will transmit the duplication to all of his daughters, to date male-to-female transmission has not been described. A male will not transmit the duplication to his sons. Offspring of either sex who inherit the GPR101 duplication will be affected. Once the GPR101 duplication has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

X-linked acrogigantism should be suspected in an individual with early-onset pituitary gigantism, defined as acceleration of linear growth due to growth hormone (GH) excess. All individuals with X-linked acrogigantism reported to date have manifested the first signs of the disorder before age four years, with most manifesting the disease during the first two years of life.

Clinical findings

• Accelerated growth velocity (>+2 SD) and/or abnormally tall stature (>+2 SD, adjusted for parental height). Note: When available, country-specific growth curves should be employed.
• Other frequently observed clinical features of GH excess: acral enlargement, coarse facial features, and increased appetite (~1/3 of cases)

Laboratory findings

• GH excess as demonstrated by:
  • Elevated levels of GH that do not suppress during an oral glucose tolerance test (OGTT) (1.75 g/kg of anhydrous glucose; maximum 75 g)
  • Increased circulating age-adjusted IGF-1 levels
• Hyperprolactinemia (seen in 26/28 reported individuals for whom data were available)

Imaging findings consistent with either of the following:

• Pituitary macroadenoma (>10 mm in diameter) with or without associated hyperplasia (in 24 of 30 reported individuals with available data)
• Diffusely (even slightly) enlarged pituitary gland secondary to pituitary hyperplasia without an adenoma (in 6 of 30 reported individuals with available data)

Note: Although none of the reported individuals presented with a microadenoma, this presentation is theoretically possible.

Histopathologic findings. Pituitary adenomas observed in X-linked acrogigantism have a peculiar sinusoidal and lobular architecture with frequent calcifications and follicle-like structures. Sparsely and densely granulated GH-secreting cells are admixed with cells secreting prolactin. Mitotic activity and the proliferation index Ki-67 are generally low [Beckers et al 2015, Iacovazzo et al 2016].

Establishing the Diagnosis

The diagnosis of X-linked acrogigantism is established in an individual with pituitary gigantism and a germline or somatic duplication of GPR101 identified by molecular genetic testing (see Table 1) [Trivellin et al 2014, Daly et al 2016b, Iacovazzo et al 2016]. Although most (not all) individuals with X-linked acrogigantism have duplications of GPR101 as well as ARHGEF6, CD40LG, and RBMX, to date it is unclear whether duplication of these other genes or the number of copies of GPR101 influence diagnosis and/or prognosis.

If the proband:

• Is female and a simplex case (i.e., a single occurrence in a family), the GPR101 duplication is usually germline (i.e., constitutional).
• Is male and a simplex case, the GPR101 duplication is usually somatic with variable levels of mosaicism. Although to date no males who are simplex cases have been identified with a de novo germline GPR101 duplication, this remains a possibility.
• Has a family history consistent with an X-linked pattern of early-onset pituitary gigantism, the GPR101 duplication is likely to be germline.

Molecular testing approaches used to identify germline and somatic duplications can include single-gene duplication testing or chromosomal microarray analysis (CMA). Note: Sequence analysis of GPR101 is not recommended as no pathogenic sequence variants have been identified to date in individuals with X-linked acrogigantism.

• Single-gene testing. Gene-targeted duplication analysis of GPR101 should be performed first on leukocyte DNA. If a GPR101 duplication is not found on testing of leukocyte DNA, testing of DNA derived from other sources (e.g., pituitary tissue [if available], saliva, skin, tissue from previous surgery) is recommended – especially in simplex males whose phenotype suggests X-linked acrogigantism – as such testing may detect a somatic mosaic GPR101 duplication not present in leukocyte DNA [Rodd et al 2016]. Note: Copy number variation droplet digital PCR is recommended as this technique can identify GPR101 duplications and low-level mosaicism with high sensitivity [Daly et al 2016b, Iacovazzo et al 2016].
• Chromosomal microarray analysis (CMA) may be used to detect genome-wide duplications (including GPR101 duplications). However, standard cytogenetic CMA may not correctly identify the GPR101 duplication in all individuals with X-linked acrogigantism:
  • In one individual with a molecularly confirmed diagnosis of X-linked acrogigantism, the length of the duplication was below the sensitivity of the standard genome-wide array employed [Iacovazzo et al 2016].
  • Low-level mosaicism may not be identified.
  Targeted CMA with a higher density of probes in the Xq26.3 region – if available – can overcome such limitations [Trivellin et al 2014, Iacovazzo et al 2016].

Clinical Description

X-linked acrogigantism is characterized by marked growth acceleration due to growth hormone (GH) excess starting at an early age (see Figure 1, Figure 2, and Figure 3). Most reported affected individuals (24/33) are females; clinical data are available for 30 individuals. In most individuals with X-linked acrogigantism GH excess results from a mixed GH- and prolactin-secreting pituitary macroadenoma (i.e., >10 mm). Less commonly, GH excess is caused by hyperplasia of the GH- and prolactin-secreting pituitary cells [Trivellin et al 2014]; six of 30 individuals with available data had pituitary hyperplasia in the absence of a pituitary adenoma.

Figure 1.

Growth curve of a female patient with molecularly confirmed X-linked acrogigantism who presented at age five years with abnormally tall stature. Her growth proceeded at a rapid pace despite treatment with somatostatin analogs (SSA) and dopamine agonists (more...)

Figure 2.

Clinical and radiologic features of individuals with molecularly confirmed X-linked acrogigantism A-D. Girl (same patient as in Figure 1) age five years who presented with abnormally tall stature and no significant coarsening of the facial features

Figure 3.

Patient age three years (right) at initial presentation, with her unaffected sister, age six years (left). The diagnosis of X-linked acrogigantism was made at age 28 years [Iacovazzo et al 2016]. From Moran et al [1990]; republished with permission of (more...)

The presenting feature in all affected individuals is growth acceleration, which can manifest as early as age two months [Trivellin et al 2014, Beckers et al 2015, Daly et al 2016a, Daly et al 2016b, Gordon et al 2016, Iacovazzo et al 2016, Naves et al 2016, Rodd et al 2016, Beckers et al 2017]. All individuals with X-linked acrogigantism have manifested the first signs of the disorder before age four years, with most manifesting during the first two years of life. There is no difference in the clinical presentation between males and females.

Other manifestations – in order of frequency – include enlargement of hands and feet, coarsening of the facial features, and increased appetite [Beckers et al 2015, Iacovazzo et al 2016]. Body mass index is also frequently increased at the time of diagnosis. Less frequently described findings are acanthosis nigricans, sleep apnea/snoring, excessive perspiration, diastema, abdominal distension, and skin thickening. Neurologic signs or symptoms are rarely present; intellectual disability has been reported in one affected individual only and was not clearly related to the GPR101 duplication [Naves et al 2016]. While all individuals with X-linked acrogigantism are prepubertal at the time of presentation, untreated older individuals with hyperprolactinemia would be expected to develop signs of hypogonadism and/or delayed puberty.

Untreated X-linked acrogigantism can lead to markedly increased stature with obvious severe physical and psychological sequelae. Moreover – as occurs in individuals with gigantism or acromegaly secondary to other causes – uncontrolled GH excess is associated with a significantly increased risk of cardiovascular, cerebrovascular, metabolic, neurologic, and orthopedic complications as well as decreased life expectancy [Tagliafico et al 2008, Killinger et al 2010, Jayasena et al 2011, Ritvonen et al 2016].

Genotype-Phenotype Correlations

To date, no genotype-phenotype correlations are evident as the clinical phenotype of the single individual harboring a smaller duplication (encompassing GPR101 only) was identical to the phenotype of other individuals whose duplications encompass GPR101 and the neighboring genes on Xq26.3 [Iacovazzo et al 2016].

While a limited number of simplex males with X-linked acrogigantism have been reported to date, no differences have been observed between individuals with germline duplications and those with somatic mosaic duplications [Daly et al 2016b, Iacovazzo et al 2016].

Penetrance

All heterozygous females and hemizygous males described to date were affected.

In females who are simplex cases, the GPR101 duplications arose de novo as demonstrated by the normal dosage of GPR101 in samples from the unaffected parents. Moreover, in the three families described, all males who inherited the duplication from their affected mother were affected. Thus, based on currently available data the penetrance for X-linked acrogigantism appears to be 100%.

Nomenclature

The abbreviation X-LAG has traditionally been used in the medical literature as an abbreviation for X-linked acrogigantism and the abbreviation XLAG for X-linked lissencephaly with ambiguous genitalia.

Prevalence

X-linked acrogigantism is extremely rare. To date, 33 individuals with a molecularly confirmed diagnosis have been reported [Trivellin et al 2014, Beckers et al 2015, Daly et al 2016a, Naves et al 2016, Daly et al 2016b, Gordon et al 2016, Iacovazzo et al 2016, Rodd et al 2016, Beckers et al 2017].

In two series of individuals with pituitary gigantism who underwent genetic testing, X-linked acrogigantism accounted for 10% of 143 affected individuals [Rostomyan et al 2015] and 8% of 153 affected individuals [Iacovazzo et al 2016].

X-linked acrogigantism accounts for approximately 20% of females with pituitary gigantism [Iacovazzo et al 2016] and approximately 65% of individuals whose symptoms appeared at or before age five years [Korbonits, unpublished data].

Evaluations Following Initial Diagnosis

To establish the extent of disease and further management needs in an individual diagnosed with X-linked acrogigantism, the following evaluations are recommended:

• Consultation with a specialist in pediatric endocrinology or endocrinology
  • Clinical assessment with special attention to signs and symptoms of growth hormone (GH) excess and hyperprolactinemia.
  • Endocrine tests including spot GH (with dilution if above detection limit of the assay), IGF-1, and prolactin to assess for disease activity. LH, FSH, estradiol/testosterone, TSH, fT4, and 9 a.m. cortisol (and if needed dynamic testing) should also be checked in order to detect associated hypopituitarism.
• Visual field evaluation to assess for mass effects due to an expanding pituitary tumor. Young children may need informal testing (e.g., observing eye movements toward small objects in different areas of the visual field).
• Pituitary MRI for evidence of pituitary hyperplasia or a pituitary tumor. In case of a pituitary tumor, extrasellar extension should be evaluated.
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Surveillance

Patients with X-linked acrogigantism require the following:

• Intensive monitoring of height and growth velocity, and frequent clinical assessment for other manifestations of GH excess (including enlargement of the extremities, hyperhydrosis, headache, joint pain) and/or enlargement of a pituitary adenoma (visual field deficits)
• Intensive monitoring of pituitary function tests (spot GH, IGF-1, prolactin) to determine disease activity and response to treatment. Note: Frequency depends on control of GH excess, clinical status, compliance with treatment, treatment modality, and presence of comorbidities.
• Periodic evaluation of basal hormone tests (9 a.m. cortisol, TSH, fT4, LH, FSH, estradiol/testosterone), and, if necessary, dynamic testing (e.g., growth hormone stimulation tests, ACTH stimulation test) to evaluate for hypopituitarism. Note: Patients treated with radical neurosurgery and/or radiotherapy may develop GH deficiency and should receive GH replacement treatment as appropriate.
• Repeat pituitary MRI. Note: Frequency depends on previous extent of the tumor, treatment modality, clinical status, and disease activity.

The established guidelines regarding surveillance for associated comorbidities and risk of secondary neoplasms for patients with acromegaly [Melmed et al 2013] should be applied to patients with X-linked acrogigantism. These include the following:

• Evaluation for associated comorbidities of GH excess (including hypertension, diabetes mellitus, sleep apnea, cardiovascular disease, osteoarthritis).
• Although this complication has not been reported in X-linked acrogigantism, adults with active acromegaly (increased GH and age-adjusted IGF-1 levels) are at higher risk of developing colonic neoplasms. Thus, colonoscopy at age 40 years is advised with further surveillance at three- to ten-year intervals depending on the presence/absence of abnormalities in the initial colonoscopy and levels of GH and IGF-1 [Cairns et al 2010].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Considering the need for multimodal treatment and the associated high frequency of hypopituitarism, women with X-linked acrogigantism may need specific fertility treatment in order to conceive.

As medical treatment does not result in significant tumor shrinkage in patients with X-linked acrogigantism, the authors recommend that women with macroadenomas undergo surgery to reduce the adenoma size prior to consideration of pregnancy.

Women with X-linked acrogigantism who have a pituitary macroadenoma may experience clinically significant enlargement of the adenoma during pregnancy. Thus, they should be questioned about symptoms that could indicate tumor growth (increased frequency of headaches, visual changes) and monitored clinically with serial visual field testing. In the presence of symptoms or new visual field abnormalities, an MRI should be performed.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

X-linked acrogigantism is inherited in an X-linked manner; however, most individuals with X-linked acrogigantism have a de novo genetic alteration not inherited from a parent.

Risk to Family Members

Parents of a female proband

• All female probands reported to date have a de novo GPR101 duplication; vertical transmission of a GPR101 duplication from an affected parent to a daughter has not been reported.
• Recommendations for the evaluation of parents of a proband with an apparent de novo GPR101 duplication include clinical evaluation and molecular genetic testing.

Parents of a male proband

• If a male is the only affected family member (i.e., a simplex case), the affected male most likely has somatic mosaicism for a GPR101 duplication and his mother is not heterozygous for the duplication. To date, all reported males who are simplex cases have a de novo somatic mosaic GPR101 duplication.
• If a male proband has an affected sib, his mother is most likely heterozygous for the GPR101 duplication. In the three reported instances of familial X-linked acrogigantism, affected males inherited the GPR101 duplication from affected mothers [Trivellin et al 2014, Gordon et al 2016]. Note: If the GPR101 duplication cannot be detected in the leukocyte DNA of a mother with more than one affected child (one of whom is male), she most likely has germline mosaicism (maternal germline mosaicism has not been reported in X-linked acrogigantism but is a theoretic possibility).
• Clinical evaluation of the mother and review of the family history may help distinguish male probands with a de novo somatic mosaic GPR101 duplication from those with an inherited germline GPR101 duplication. Molecular genetic testing of maternal leukocyte DNA can determine if the mother is heterozygous for the GPR101 duplication.
• The father of an affected male will not have the disorder nor will he be hemizygous for the GPR101 duplication; therefore, he does not require further evaluation/testing.

Sibs of a female proband

• Risk to sibs depends on the genetic status of the parents.
• All females reported to date have had a de novo GPR101 duplication, suggesting a low risk to sibs; however, risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of germline mosaicism in one of the parents.

Sibs of a male proband. Risk to sibs depends on the genetic status of the mother:

• If the mother of a male proband is not affected and the proband represents a simplex case (i.e., a single occurrence in a family), sibs are presumed to be at low risk as all simplex males reported to date have a somatic mosaic GPR101 duplication. However, risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of maternal germline mosaicism.
• If the mother of the proband is affected/has the GPR101 duplication, the chance of transmitting it in each pregnancy is 50%. Female and male sibs who inherit the GPR101 duplication will be affected (see Penetrance).

Offspring of a female proband. Each child of a female with X-linked acrogigantism has a 50% chance of inheriting the GPR101 duplication.

Offspring of a male proband

• If a male proband has a somatic mosaic GPR101 duplication that involves germ cells, he could theoretically transmit the duplication to his daughters (who would be affected).
• A male proband with a germline GPR101 duplication will transmit the duplication to all of his daughters (who will be affected).
• A male proband will not transmit the duplication to his sons.

Other family members. Given that most probands with X-linked acrogigantism reported to date have the disorder as a result of a de novo GPR101 duplication, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

Prenatal Testing and Preimplantation Genetic Testing

Once the GPR101 duplication has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The individuals originally described with X-linked acrogigantism harbored duplications of chromosome Xq26.3 with a smallest region of overlap (SRO) encompassing four genes (ARHGEF6, CD40LG, GPR101, and RBMX) [Trivellin et al 2014]. Of these genes, only GPR101 was significantly overexpressed in the pituitary samples of affected individuals.

More recently, an individual with a typical phenotype and a complex genomic rearrangement was described [Iacovazzo et al 2016]. In this individual, high-density chromosomal microarray analysis revealed a proximal duplication followed by a normal copy segment and a distal duplication. The distal duplication allowed the definition of a novel SRO encompassing GPR101 only, and not the neighboring genes on Xq26.3, thus proving the pathogenic role of GPR101.

Microhomologies, small insertions, or complex genomic rearrangements were identified at the breakpoint junctions in most individuals with X-linked acrogigantism. These mutational signatures suggest fork stalling and template switching/microhomology-mediated break-induced replication (FoSTeS/MMBIR) as the causative mechanism [Trivellin et al 2014, Daly et al 2016b]. In one individual, the duplication was generated via an Alu-Alu mediated rearrangement [Iacovazzo et al 2016].

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Author Notes

Website: www.fipapatients.org

The FIPA patients website, established by Dr Korbonits in collaboration with the FIPA Consortium, is an information resource for patients and families with familial isolated pituitary adenoma (FIPA) and other rare conditions predisposing to pituitary adenomas. It also provides general information for medical professionals on research in this field, including links to relevant publications.

The authors welcome comments and inquiries to gro.stneitapapif@ofni.

Contact information for the laboratories that originally reported the genetic etiology of X-linked acrogigantism and continue to actively conduct research on the condition is provided below:

Dr Constantine A Stratakis' laboratory
NIH/NICHD, DEB, SEGEN
10 Center Drive, CRC, Rm 1E-3216
Bethesda, MD 20892-1862 USA
Email: stratakc@cc1.nichd.nih.gov; giampaolo.trivellin@nih.gov
Phone: 301-402-1998; 301-451-8034
Website: Pediatric Gigantism and Acromegaly

Prof Albert Beckers' laboratory
Department of Endocrinology CHU Sart Tilman B35
Domaine Universitaire du Sart-Tilman
University of Liège, 4000 Liège, Belgium
Email: albert.beckers@chu.ulg.ac.be; adrian.daly@ulg.ac.be
Phone: 0032 4 3667083

Acknowledgments

We are grateful to referring colleagues and patients for providing information on this disease. We gratefully acknowledge Dr Celia Rodd (University of Manitoba, Winnipeg, Canada) and Dr Christine Burren (University Hospitals Bristol NHS Foundation Trust, Bristol, UK) for providing the patients' pictures.

Revision History

• 1 February 2018 (bp) Review posted live
• 19 October 2016 (mk) Original submission