Mean age at onset in our unselected series of 122 FSHD patients was 23 years, with a wide range from childhood to adulthood (). When the 76 index cases were considered separately from their 46 affected relatives, mean age at onset was 21 years (range: 4–60). Instead, in affected relatives it was 26 years (range: 9–56).
As shown in , scapulo-humeral muscle weakness was reported at onset in 80 out of 122 cases. In all, associated signs of facial weakness were clearly demonstrable at initial neuromuscular examination. Weakness was asymmetrical in 32 of these 80 cases (40%). Their mean EcoRI fragment was 24 kb, ranging from 14 to 38. In only eight cases (7%), facial weakness was the predominant clinical manifestation at onset. However, when first examined, all these patients also showed variable degrees of weakness in the scapulo-humeral region. Their EcoRI fragment had a mean value of 18 kb (range: 14–30). Altogether, disturbances related to facial or scapulo-humeral weakness, which are the typical onset disorders according to the FSHD diagnostic criteria of the European Neuromuscular Centre 
, were reported to be the presenting symptoms by 88 of our 122 symptomatic FSHD patients (72%).
FSHD clinical onset: the predominant types.a
In seven cases (), the disease showed a late-onset presentation at a mean age of 39, with shoulder-girdle weakness in the absence of facial involvement. This “facial-sparing” phenotype appeared persistent over a mean disease course of 24 years. In these patients the EcoRI fragment size (mean value 36 kb, range: 32–38 kb) indicated a very small 4q35 deletion.
Some data of 18 FSHD patients with non-typical onset.
Foot drop was recollected as the first clinical symptom by 16 of our 122 cases (13%), mostly unilaterally (12/16 cases: see ). This type of onset was only experienced by index cases (9 males and 7 females), with a mean age at onset of 27 years (range: 10–53). Moreover, at first neurological evaluation scapulo-humeral or facial weakness was detected in all but one index case. The EcoRI fragment in these patients had a mean value of 27 kb (range: 19–38).
Onset with atypical proximal weakness in the lower limb muscles was reported by eight patients (7%), as shown in . They were all females with a mean age at onset of 36 years (range: 15–64). All were index cases, mostly with bilateral weakness of the quadriceps muscle and less involvement of the iliopsoas. At first neurological examination, associated weakness in the scapulo-humeral muscle region was identified in all of them. Likewise, all showed variable facial muscle deficit. In these eight cases, the 4q35 fragment ranged from 15 to 27 kb (mean 22 kb).
Clinical presentation with unilateral sural triceps involvement was evident in only one of our FSHD subjects. The clinical features of this 43-year-old man are listed in (case 1). Since age 21, he had difficult walking on tip-toes and standing on his left leg. Since the disturbance was associated with altered serum CK (three-fold the normal value) he was referred to our outpatient clinic for neurological evaluation. His neuromuscular examination showed moderate left leg triceps weakness and hypotrophy without other abnormalities. His fraternal twin brother, who had already been diagnosed elsewhere with FSHD, showed moderate weakness of the scapulo-humeral muscles; he had complained of these disturbances since adolescence. Evaluation of the EcoRI fragment (38 kb) revealed a small 4q35 deletion in both brothers.
Quite atypical onsets were reported by two FSHD subjects. The first (cases 2, ) was a 42-year-old woman, whose mother suffered from a mild form of FSHD myopathy and rare sporadic grand mal seizures. The patient had long been considered affected by an idiopathic encephalopathy. She had been treated with antiepileptic drugs since her first year of life due to tonic or tonic–clonic seizures. Moreover, her psychomotor development was delayed, with ability to walk at three and to speak a few words at five years of age. There were no evident causes of brain pathology either in the clinical history (pregnancy and perinatal period uneventful) or from analysis of her karyotype (no chromosomal abnormalities). Her IQ score was 0.36 at 16 and 0.34 at 38 years of age. Interictal EEG findings were normal, aside from a few occasions (at 7, 15 and 35 years) when brief diffuse discharges of spikes and polyspikes were detected. At 38, her brain MRI was normal. Hearing loss had also appeared in early childhood. Some facial weakness was evident before age five, while difficulty in arm abduction and other signs of shoulder-girdle muscle weakness had appeared at age 14. At present, she walks independently with a mixed stepping and waddling gait and can abduct her arms by 70°. Facial weakness and mild bilateral foot drop are also evident. Analysis of her DNA identified a 4q35 fragment of 11 kb. Some clinical details of this case have been described in a previous report on the infantile variant of FSHD 
A myoglobinuric attack during adolescence characterized disease onset in a 41-year-old man (cases 3, ). At 18 years of age, he suffered from acute rhabdomyolysis triggered by prolonged muscle activity. Urinalysis indicated massive myoglobinuria. The patient improved but clinical investigations failed to identify any recognized cause of myoglobinuria, including infections, exposure to drugs or toxic factors, trauma or inherited errors of metabolism. After recovery, his neurological examination revealed only a mild hypotrophy of the left leg muscles. Muscle biopsy showed no glycogen or lipid storage and no evidence of mitochondrial myopathy. Normal biochemistry of muscle phosphorylase, phosphofructokinase and carnitine-palmitoyl-transferase ruled out the relative metabolic causes of myoglobinuria. Routine muscle histology showed non-specific myopathic changes. In the following years, immunoblot analyses of dystrophin, dysferlin, sarcoglycans, caveolin yielded normal results. At 30 years of age, he developed impaired arm abduction, suggesting the diagnosis of FSHD. His DNA examination confirmed the clinical diagnosis revealing a 4q35 fragment of 24 kb, inherited from his asymptomatic father. Since FSHD did not provide an adequate explanation for rhabdomyolysis at onset, a complete molecular study of the calpain3 gene (CAPN3) was also carried out in muscle DNA. The molecular analysis, performed as elsewhere reported 
, revealed an heterozygous mutation in CAPN3 exon 4 (c.505C>T R169C), in addition to the previously identified FSHD 4q35 deletion.
In all our patients with atypical onset, clinical heart examination and 24-h ECG Holter monitoring gave normal results. Previous cardiologic assessment in the majority of the patients included in the present investigation has been described earlier 
compares the main findings of our clinical research with those of two similar studies reported to date on series of FSHD cases with 4q35 analysis [10,11]
. In the first, Butz et al. 
re-evaluated 39 patients, confirming the FSHD diagnosis in 34 with an EcoRI fragment ranging from 32 to 41 kb; they searched among them for possible non-typical FSHD phenotypes according to the FSHD diagnostic criteria of the European Neuromuscular Centre 
. The aim of Krasnianski et al.’s 
clinical investigation was to analyze the occurrence of atypical clinical presentations among 41 unselected FSHD patients with an EcoRI fragment size lower than 35 kb. mainly underlines the divergent results yielded by the three investigations on the types of atypical presentation.
Type of disease onset: comparison of our study with the two reports on FSHD series of cases with 4q35 analysis.