Clinical and genetic characteristics of 42 Chinese paediatric patients with X-linked adrenal hypoplasia congenita

Clinical characteristics and treatment of PAI

All 42 patients with X-linked AHC from 39 non-consanguineous families were male, including 39 with isolated DAX1 defects from 36 unrelated families and three with Xp21 deletions. They were from 13 provinces across China (Table 1). Of the 42 patients, the median age of onset and of diagnosis was 1.0 month (range: 0.0–98.0) and 3.0 years (range: 0.1–15.0), respectively. The duration of the follow-up was 7.7 ± 4.5 years, and the age of the patient with the last follow-up was 9.0 ± 5.0 years old.

Table 1 Clinical features and genetic data of 42 patients with X-linked AHC

The most common initial feature was hyperpigmentation presenting in 90% (38/42) of the patients, followed by vomiting/diarrhoea in 48% (20/42), failure to thrive in 31% (13/42), and convulsions in 17% (7/42). Biochemical results showed increased ACTH levels [60% (25/42) over 1250 pg/ml] in all patients (42/42), decreased cortisol levels [63.1 (21.7–139.3) nmol/L] in 88% of patients (37/42), decreased serum sodium levels (126.7 ± 8.9 mmol/L) in 76% of patients (32/42) and increased serum potassium levels (6.0 ± 1.4 mmol/L) in 69% (29/42) of patients (Table 1).

An apparent bimodal distribution pattern for age at presentation was observed in 42 patients with X-linked AHC. Of those, 31 cases (74%) presented within one year of age with a median age of 15.0 days (range: 0.0–1.0 year), while 11 cases (26%) presented over three years of age with a median age of 4.5 years (range: 3.0–8.2). Therefore, 42 patients were divided into the infantile-onset group (≤ 1 year) and the childhood-onset group (> 1 year) according to the onset age (Table 2). There was no significant difference between these two groups in the frequency of all the signs/symptoms (all P > 0.05). In addition, a comparison of the biochemical parameters displayed no significant difference in the serum sodium and cortisol levels (both P > 0.05), but the serum potassium level of the infantile-onset group was higher than that of the childhood-onset group (6.3 ± 1.4 mmol/L vs. 5.1 ± 0.9 mmol/L, P = 0.0033). This finding indicated that the degree of electrolyte disturbance in infantile-onset patients was more severe than that in childhood-onset patients with X-linked AHC.

Table 2 Clinical and biochemical features of 42 patients with X-linked AHC

The hydrocortisone (HC) and 9α-fludrocortisone replacement therapy was a crucial treatment for adrenal dysfunction in all patients, and the doses were 13.3 ± 2.9 mg/m2/d and 0.05 (0.05–0.05) mg/d, respectively. Patients over 14 years of age (n = 13) had higher doses of HC than those under 14 years old (n = 29) (15.4 ± 2.7 mg/m2/d vs. 12.3 ± 2.5 mg/m2/d, P = 0.0027). After the treatment, all the patients showed remission in clinical signs and symptoms of PAI, hyperpigmentation disappeared gradually, and the serum electrolyte levels returned to normal, although the ACTH level [305.0 (54.3–539.0) pg/ml] remained mildly high.

Evaluation of pubertal development and treatment for HH

Among the 42 patients, thirteen patients were over 14 years of age and were assessed for the conditions of pubertal development (Table 3). In these 13 patients, three exhibited spontaneous pubertal development, and ten encountered delayed puberty.

Table 3 Pubertal development in 13 patients and treatment for HH in seven patients

Spontaneous adolescent development was observed in three patients (P2, P9, and P10) during the follow-up at the age of 12.5 ± 0.3 years, with a testicular volume of 5.0 (5.0–5.5) ml, basal FSH level of 10.50 ± 1.35 IU/L, LH level of 0.98 ± 0.39 IU/L, and the testosterone level was 3.93 ± 1.61 nmol/L. The age of the last follow-up of these three patients was 15.6 ± 1.2 years old. Patient 2 was found to have pubertal arrest, with a decrease in testicular volume (from 6 to 3 ml) and testosterone level (from 5.79 nmol/L to 0.49 nmol/L) at 17.3 years old, suggesting arrested puberty. The peak LH and FSH levels after the GnRH stimulation test were 3.66 IU/L and 9.19 IU/L, respectively, suggesting the onset of HH. The other two patients (P9 and P10) had slow pubertal progression, and their testes were still around Tanner stage 2–3 (testicular volumes of 6 ml and 8 ml, respectively) two years after puberty initiation (Table 3). Ten patients with delayed puberty exhibited reduced testicular volume (2.6 ± 0.5 ml), low basal LH levels [0.23 (0.15–0.24) IU/L] and reduced testosterone production [< 0.35 nmol/L in all but one patient (P34, 0.62 nmol/L)] at 14.1 years of age (range: 14.0–15.3), suggesting the presence of HH. Of those patients, seven patients underwent the GnRH stimulation test, none of whom responded, with a peak FSH level of 1.93 (1.66–3.59) IU/L and a peak LH level of 0.59 (0.19–1.00) IU/L. These ten patients had significantly decreased testicular volume, basal FSH, LH, and testosterone levels compared to the three patients with spontaneous pubertal development (P = 0.0160, 0.0070, 0.0140, 0.0028, respectively). Therefore, in this cohort, eleven of the 13 patients over 14 years old had HH, including ten with delayed puberty and one with spontaneous pubertal development followed by disrupted puberty.

For the management of 11 patients with HH, four accepted hCG treatment (P11, P14, P23, and P34), and three received pulsatile GnRH administration (P16, P20, and P32). Of these three patients with pulsatile GnRH treatment, two patients (P20 and P32) had received hCG previously for 2.5 years and 6 months, respectively, but with limited effects. Thus, six patients had been treated with hCG. In addition, patient 2 recently underwent hCG therapy for less than one month, patient 21 received testosterone replacement, and the other two patients (P3 and P37) did not receive any management for HH. Therefore, a total of four patients (P2, P3, P21, and P37) had no data on treatment outcomes.

Six patients who received hCG therapy for 6.5 (6.0–24.3) months exhibited an enlargement of testicles from 2.7 ± 0.4 ml to 3.3 ± 0.4 ml (P = 0.0250). Their total testosterone levels increased from < 0.35 nmol/L in all but one patient (P34, 0.62 nmol/L) to 1.99 (1.20–2.91) nmol/L (P = 0.0313), which were still below the normal range for age in all patients except for one (P34, 14.86 nmol/L). The FSH and LH levels showed no change. This suggests that the increase in testicular volume and testosterone levels in the patients after hCG treatment was limited.

Three patients underwent pulsatile GnRH administration for 2.7 ± 1.5 months. A mild increase in testicular volumes [from 3.0 (3.0–3.3) ml to 4.5 (4.5–6.8) ml], basal LH levels [from 0.23 (0.12–0.31) IU/L to 1.77 (1.36–2.60) IU/L], basal FSH levels [from 2.84 ± 1.27 IU/L to 6.19 ± 2.39 IU/L], and testosterone levels [from all < 0.35 nmol/L to 1.43 (1.28–3.00) nmol/L] was observed (Fig. 2). There was still no response to the GnRH stimulation test in these three patients, with the peak LH level increasing from 1.21 ± 0.56 IU/L to 1.28 ± 0.57 IU/L and peak FSH level increasing from 4.40 ± 2.23 IU/L to 6.32 ± 2.99 IU/L. Thus, all three patients had some growth in terms of testicles, basal hormone levels, and GnRH-stimulated peak LH and FSH levels when comparing pre- and post-pulsatile GnRH treatment, although no significant difference was observed (all P > 0.05), probably due to the small sample size.

Fig. 2figure 2

Treatment effects of pulsatile GnRH in three patients. Testicular volume (A), testosterone (B), LH (C), and FSH (D) changes before and after pulsatile GnRH treatment. P16 solid grey line; P20 black dotted line; P32 solid black line

We compared the final testicular volume, LH, FSH, and testosterone levels between the six patients receiving hCG therapy at the last follow-up (n = 4) or prior to the therapy alteration (n = 2) and in three patients undergoing pulsatile GnRH administration at the last follow-up (n = 3). The testicles and LH levels of the patients undergoing pulsatile GnRH were larger and higher than those undergoing hCG therapy [4.5 (4.5–6.8) ml vs. 3.3 ± 0.4 ml, P = 0.0243] [1.77 (1.36–2.60) IU/L vs. 0.65 (0.23–0.77) IU/L, P = 0.0476]. Thus, pulsatile GnRH may be recommended for HH when hCG therapy is not satisfactory, although it is difficult to achieve normal testicular volume. Despite this, the height SDS of these 7 patients increased significantly after hCG medication and/or pulsatile GnRH therapy (− 1.82 ± 1.18 vs. − 0.87 ± 1.02, P = 0.0444), possibly due to the elevated testosterone levels after treatment.

Genetic assessment 1.

Xp21 deletion syndrome

Three patients (P37, P38 and P39) with Xp21 deletion syndrome were diagnosed by chromosomal microarray assays (Table 1). P37 showed hyperpigmentation and vomiting at 3.3 years old. When he was five years of age, a detailed clinical and biochemical examination was performed, which indicated mild intellectual disability, normal urinary glyceric acid and creatine kinase levels and adrenal dysfunction. Therefore, he was considered to have Xp21 deletion syndrome and diagnosed with IL1RAPL1 and DAX1 deletions (3.3 Mb) by CMA. He is currently 14.2 years of age, affected by intellectual disability and HH in addition to adrenal failure.

P38 presented with hyperpigmentation after birth and failure to thrive during the neonatal period. When he was six months of age, he manifested with delayed milestones (unable to lift his head) and hypotonia coupled with adrenal insufficiency. His two elder brothers had died at the ages of two months and four months. The laboratory findings showed that urinary glyceric acid level was elevated and creatine kinase in the blood was 5645 IU/L (reference range: 39–308 IU/L). Thus, Xp21 deletion syndrome was suspected by these clinical findings, and he was further diagnosed with IL1RAPL1, DAX1, GK, and DMD deletions (3.1 Mb) through CMA. Unfortunately, he died at the age of six months due to an adrenal crisis.

P39 encountered hyperpigmentation after birth. When he was two years old, he presented with failure to thrive and hypotonia, with a length of 80 cm (< − 2SD) and a weight of 8.8 kg (< − 2SD). Biochemical findings showed that the serum creatine kinase level was 9431 U/L and that the urinary glyceric acid level was 653.16 (reference range: 0.0–20.0 mmol/mol creatinine). His developmental quotient (DQ) scores in the domains of adaptive behaviour, gross motor, fine motor, language, and social behaviour assessed by the Gesell Development Diagnosis Scale were 23, 23, 25, 35, and 37, respectively, suggesting severe developmental delay. He was further diagnosed definitively with IL1RAPL1, DAX1, GK, and DMD (3.6 Mb) deletions by CMA. He is currently four years old, speaks few words and is unable to walk due to intellectual disability and persistent hypotonia.

2.

DAX1 variant spectrum

A total of 30 variants in the DAX1 gene were identified in 42 patients, including missense (n = 6), nonsense (n = 6), frameshift (n = 14), and gross deletions (n = 4), which were all classified as pathogenic (P) or likely pathogenic (LP) (Table 1, Fig. 3). Of the 30 DAX1 variants, the entire DAX1 deletion was the most frequent variant (10/42, 23.8%). Fourteen variants were not reported previously [28]. Frameshift and nonsense variants were distributed throughout the DAX1 gene, located at both the DBD and LBD domains, whereas missense variants clustered in the LBD domain (Fig. 3).

Fig. 3figure 3

Twenty-six identified DAX1 variants (frameshift, missense, and nonsense variants) in 30 patients. DBD DNA-binding domain; LBD putative ligand-binding domain; novel variants are in bold

Of the 42 patients, 18 had frameshift variants, six had nonsense changes, and six had missense changes. The remainder (n = 12, 29%) had a deletion of the locus containing DAX1. Seven of these deletions involved the entire DAX1 gene, and two large deletions contained only exon 2 of DAX1, whereas three patients (P37, P38, and P39) harboured a contiguous gene deletion. Among these three patients, one (P37) had a deletion of IL1RAPL1 and DAX1, and two (P38 and P39) carried the deletion extending distally to include the IL1RAPL1, DAX1, GK, and DMD loci.

3.

Genotype–phenotype analysis

First, nine patients with a deletion involving DAX1 alone presented with isolated X-linked AHC, while two patients (P38 and P39) at risk for the metabolic crisis or phenotypic characteristics of hypotonia and ID were found to have the deletion extended to contain the IL1RAPL1, DAX1, GK and DMD genes. A deletion extending to IL1RAPL1 and DAX1 was confirmed in one patient (P37) exhibiting ID in addition to adrenal dysfunction. Thus, a good genotype–phenotype correlation was confirmed in Xp21 deletion syndrome.

Then, an attempt was made to associate the severity of the disorder with specific variants. The age of onset of patients with X-linked AHC was used to assess the severity of adrenal insufficiency since it is the most readily available proxy. Of seven patients with isolated entire DAX1 deletion and three with Xp21 deletion, all except for one patient (P37) had an early onset age of less than one year, indicating that the entire DAX1 deletion might be associated with early onset age. In addition, no relation was found between the type of DAX1 variant and whether pubertal development can be initiated spontaneously.

Finally, patients within a pedigree carrying the same variant may have different ages of onset. Patient 5A with the c.501del variant presented at one year of age, while his younger cousin (P5B) presented at 3.3 years of age. The age of onset of patient 8C with the c.676del variant was three years, while the age of onset of his younger cousins (P8A and P8B) was within the first five days and three days of life, respectively. It elucidated the phenotypic heterogeneity of X-linked AHC. In terms of phenotypic heterogeneity, genetic changes, epistatic interactions, and additional modifier variants may influence disease presentation in some single gene disorders. Although a group of modifier variants may influence the phenotype, not every modifier variant will be involved in every patient, implying a role for oligogenic inheritance in phenotypic expression [29, 30].

留言 (0)

沒有登入
gif