Hurler syndrome (MPS 1H)
Two MPS 1H patients were diagnosed with GHD and treated with rhGH in our Centre. They both received treatment with ERT in the first months of life followed by early HSCT. Both these patients received a busulphan−/cyclophosphamide-based myeloablative conditioning regimen before HSCT.
Patient 1 was started on ERT at the age of 15 months and underwent HSCT at 20 months of life. Due to a precocious loss of engraftment, a second HCST was successfully performed at the age of 2.8 years and adequate levels of circulating enzyme during the subsequent 11 years follow-up confirmed the stable persistence of engraftment.
At the age of 6.7 years, the combination of progressive growth deceleration at clinical review (height velocity: 1.8 cm/year, − 5.14 SDS), IGF-1 levels below − 2 SDS and a remarkably delayed bone age (4.5 years compared to a chronological age of 6.7 years), prompted the clinicians to perform arginine and dexamethasone stimulation tests, which confirmed the diagnosis of GH deficiency (GH peaks achieved: 7.9 and 4.4 microg/L, respectively).
MRI showed a normal appearance of the hypothalamic-pituitary area.
She was therefore started on a standard dose of rhGH (0.025 mg/kg/die) and it was followed by a normalization of IGF-1 levels at subsequent biochemical follow-up, with IGF-1 SDS persistently between + 1.5 and + 1.9 SDS.
Figure 1a shows patient’s growth chart before and after starting rhGH. The remarkable increase in height velocity recorded at 6 months (4.3 cm/year, − 2.11 SDS) and 12 months (5.2 cm/year, − 0.60 SDS) follow-up led to a mild improvement in height SDS (from − 3.57 to − 3.42 SDS after 12 months of treatment). While during the first 1.5 years of treatment the above-mentioned decline in height SDS was interrupted by the start of rhGH administration, a further progressive drop in height SDS was noticed subsequently and led the clinician to discontinue recombinant GH treatment at the age of 9.6 years given the overall poor late response (total duration of treatment: 2.9 years). The patient was pre-pubertal (Tanner’s stage: B1P1A1) before being started on treatment and the first early signs of pubertal development were noticed after the discontinuation of rhGH.
From an orthopaedic point of view, the skeletal abnormalities firstly found in early infancy showed a progressive worsening all throughout childhood.
A bilateral (right>left) coxofemoral sub-luxation was noticed 2 years before starting rhGH. A leg length discrepancy of about 1 cm was noticed about 2 years after the start and 1 year before the discontinuation of treatment. At last orthopaedic follow-up (3 years after the discontinuation of rhGH), the discrepancy had increased to 2 cm.
Also bilateral genu valgum showed a gradual worsening, but most of the progression occurred after the discontinuation of rhGH: a pre-treatment tibiofemoral angle of − 8° decreased to − 10° 6 months after the end of treatment and to − 12/− 15° at last orthopaedic follow-up, almost 3 years later.
Multiple vertebral malformations and T12-L1 spondylolisthesis had already been described in this patient since the age of 4 years.
Radiological follow-up showed further worsening of sagittal vertebral alignment about 1.5 years after rhGH discontinuation. Six months later (2 years after rhGH discontinuation), the patient started to complain about sporadic episodes of back-pain and lower limbs hyposthenia; hyporeflexia and progression of kyphosis were described at physical examination. The onset of clinical pyramidal signs raised the strict indication of a surgical treatment, at the age of 12.1 years.
In patient 2, ERT was started at the age of 13 months, while HSCT was performed 3 months later. The patient was diagnosed with GH deficiency when she was 6.4 years (GH peak at arginine test: 6.0 microg/L; GH peak at insulin tolerance test: 7.8 microg/L). Patient’s bone age, assessed at diagnosis of GH deficiency, was slightly delayed (5.0 years compared to a chronological age of 6.4 years). No abnormal findings involving the hypothalamic-pituitary area were noticed at MRI.
The start of rhGH was followed by a remarkable increase in height velocity: from 2.96 cm/year (− 3.44 SDS) at time 0 to 9.97 cm/year (+ 4.56 SDS) in 6 months’ time and 6.99 cm/year (+ 1.21 SDS) at the end of the first year of treatment. The initial decrease in height SDS that the patient had experienced between 5 and 6 years was interrupted by the start of recombinant GH and the patient’s growth kept on tracking the 10th centile until the age of 10.1 years, when she achieved menarche. Therapy with rhGH was discontinued when she was 11.0 years, as annual height velocity had dropped below 2 cm/year. IGF-1 levels rose from a baseline level of − 1.7 SDS to + 1.3–1.7 SDS during treatment.
Figure 1b shows the growth pattern reported for this patient. The steep increase in height showed after rhGH discontinuation is the consequence of the spinal surgical intervention she underwent at the end of growth.
From an orthopaedic point of view, a double kyphotic cervical curvature and lumbar scoliosis were noticed well before the rhGH treatment. Annual follow-up was performed during and after discontinuing rhGH and no worsening of spinal malformation was reported. As previously stated, the patient successfully underwent elective surgical correction of spinal kypho-scoliosis at the end of growth.
During the second year of life, hip X-rays showed initial coxo-femoral sub-luxation. Radiological follow-up highlighted a progressive worsening of these malformations before starting rhGH, with a more remarkable involvement of right femoral head and subsequent increasing leg length discrepancy. At the end of growth, right femoral head subluxation was radiologically more pronounced, but never progressed into overt luxation.
Morquio syndrome (MPS IV)
A single patient with Morquio syndrome has been found to be GH-deficient at our centre (patient 3).
As shown in Fig. 2, after an early satisfactory growth during the first year of life, the patient experienced a significant decrease in height velocity. She underwent arginine stimulation test at the age of 5.3 years, which provided a normal peak. After a complete arrest of growth between 7.3 and 8.9 years, the patient was re-tested and GH deficiency was confirmed (arginine test: GH peak 5.7 microg/l; dexamethasone test: GH peak 6.1 microg/L). The radiological finding of a remarkably delayed bone age (6 years, compared to a chronological age of 8.3 years) was consistent with the diagnosis of GH deficiency.
Baseline IGF-1 SDS before starting rhGH was − 2.1 SDS. MRI highlighted a dysmorphic appearance of the sella and the sphenoid bone, as consistent with MPS morphology, with normal anatomy and volume of both adeno- and neurohypophysis.
After starting her on rhGH (initial dose: 0.027 mg/kg/die), height velocity showed a remarkable increase, from 0.16 cm/year (− 6.12 SDS) to 3.33 cm/year (− 1.33 SDS) at last clinical follow-up, 24 months later. These auxological findings were consistent with a normalization of IGF-1 SDS during treatment (+ 1.0 to + 1.5 SDS).
The progressive decrease in height SDS experienced between 4.1 and 8.9 years was therefore reverted by hormonal replacement treatment (Fig. 2a and b).
From an orthopaedic point of view, the patient did not experience any complication after 24 months of treatment with rhGH. Genu valgum was surgically corrected before starting the patient on hormonal treatment and no changes were described at subsequent radiological follow-up; coxa valga was diagnosed before starting rhGH and no further worsening described later on.
In addition, the repetition of a dual-energy X-ray absorptiometry (DXA) scan 1 and 2 years after starting rhGH showed a progressive improvement of bone mineral density: total body bone mineral density z-score raised from − 4.9 observed 1 month before starting rhGH to − 3.7 (1.6 years later) and − 2.3 (2.4 years later).
Maroteaux-Lamy syndrome (MPS VI)
One female patient was started on rhGH due to demonstrated GH deficiency in our Centre (patient 4). The child had grown regularly during the first years of life (tracking the 50th centile for general population - CDC growth charts). After the age of 6 years, her height SDS began to show a progressive decrease. At the age of 8.8 years, she therefore underwent GH stimulation tests, which confirmed the diagnosis of GH deficiency (arginine test: GH peak 3.7 microg/L, dexamethasone test: GH peak 7.4 microg/L). Hand and wrist X-ray, performed at diagnosis of GH deficiency, showed a bone age of 7.8 years. Neither sellar nor juxtasellar abnormalities were noticed at MRI.
Treatment with rhGH was started at the age of 8.8 years. After the start of treatment, height velocity showed a remarkable increase (from − 4.32 SDS to − 0.95 after 6 months and + 0.95 at the end of the first year of treatment). This response reverted the previous trend towards a progressive decrease in height SDS and was therefore followed by a regular growth (height stably around + 1.3 SDS for disease-specific charts between 8.8 and 11.75 years, at last clinical follow-up) (Fig. 3a and b). IGF-1 SDS values fell within the normal range before (+ 1.1 SDS) and after (+ 1.4 to 1.9 SDS) starting rhGH.
From an orthopaedic point of view, a dorso-lumbar scoliosis diagnosed during the first years of life was treated conservatively with a back brace. In addition, genu valgum diagnosed before starting growth hormone replacement therapy was treated surgically with hemiepiphysiodesis, with a positive short- and long-term outcome; the overall orthopaedic picture showed no signs of progression after 3.8 years of treatment with rhGH.
Finally, the DXA scans performed before starting rhGH and 2.1 years later showed a remarkable increase in bone mineral density (total body bone mineral density z-score from − 1.4 to − 0.5).